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Phenotypic Variability (phenotypic + variability)
Kinds of Phenotypic Variability Selected AbstractsVariability in bleeding phenotype in Amish carriers of haemophilia B with the 31008 C,T mutationHAEMOPHILIA, Issue 1 2009A. SHARATHKUMAR Summary., The aim of this study was to characterize the variability of bleeding phenotype and its association with plasma factor IX coagulant activity (FIX:C) in haemophilia B carriers in a large Amish pedigree with a unifying genetic mutation, C-to-T transition at base 31008 of the factor IX gene (Xq27.1,27.2). A cross-sectional survey of haemophilia B carriers included a multiple choice questionnaire evaluating symptoms of mucocutaneous bleeding, joint bleeding and bleeding after haemostatic stress [menstruation, postpartum haemorrhage (PPH), dental extractions and invasive surgeries]. Severity of bleeding was graded as 0 to 4, 0 being no bleeding whereas 4 being severe bleeding. Association between total bleeding scores and the FIX:C was evaluated. Sixty-four haemophilia B carriers participated in this study. Median age: 18 years (range 1,70 years); median bleeding score: 1 (range 0,8). Besides PPH, isolated symptoms of bruising, epistaxis, menorrhagia and postsurgical bleeding including dental extraction were not associated with lower FIX:C. Bleeding score ,3 was associated with involvement of at least two bleeding sites and a lower mean FIX:C of 42 ± 10.3% (95% CI 36.4,47.7) while a score >3 had involvement of ,2 sites and higher mean FIX:C of 54.9 ± 21.5% (95% CI 49,61), P = 0.005. Subcutaneous haematoma formation and bleeding after haemostatic stress requiring treatment were associated with bleeding scores ,3. Phenotypic variability existed among the carriers of haemophilia B who belonged to a single pedigree carrying a single unifying mutation. The utility of bleeding scores to define bleeding phenotype precisely in haemophilia B carriers needs further evaluation. [source] Diversity in five goat populations of the Lombardy Alps: comparison of estimates obtained from morphometric traits and molecular markersJOURNAL OF ANIMAL BREEDING AND GENETICS, Issue 3 2001P. Crepaldi Phenotypic and genetic variability were studied within and between the goat populations of Bionda dell'Adamello, Frisa, Orobica, Verzaschese and Val di Livo. These are populations reared for most of the year on pastures of the Lombardy Alps, numbering a minimum of 1000 and a maximum of 8000 individuals per breed. The first four are standardized breeds of recent formation; at present they are supported by the European Union measures for the conservation of rare breeds. On the basis of its visible genetic profile the Val di Livo goat may be classified as a primary population. Phenotypic variability was estimated on the basis of six somatic measurements on 60,140 adult goats per breed, whereas genetic variation was measured on the basis of 201 AFLP loci. The partition of the total molecular variation into the within and between breed components indicates that the majority of the molecular variability is conserved within populations, whereas only 8.8% can be attributed to between population variation. Morphometric and molecular marker data produced unrelated distance values and different topology of UPGMA clusters. It may be hypothesized that the morphometric originality of the Val di Livo goat is mostly determined by environmental factors and selection pressure rather than by different origin and genome evolution. Conversely Orobica seems to have diverged from the other breeds at the genome level, which may be explained by an undocumented Southern Italian origin. An objective evaluation of conservation priorities may in the near future be based on the integrated use of molecular markers and of information on quantitative traits and allelic variation with adaptive relevance. Diversité dans cinq populations de chèvres des Alpes lombardes: comparaisons entre estmations obtenues par des mesures somatiques et par des marqueurs moléculaires On a etudié la variabilité phénotypique et génétique entre et parmi les populations de chèvres Bionda dell'Adamello, Frisa, Orobica, Verzaschese et Val di Livo. Il s'agit de populations qui content entre 1000 et 8000 sujets, elevés pour la plus part de l'année sur les pâturages des Alpes de Lombardie. Les quatre premières, actuellement sauvegardées par des mesures communautaires, sont des races à standard recemment constituées. La chèvre de la Val di Livo peut être rangée parmi les races primaires. La diversité phénotypique a été montrée par un dendrogramme obtenus des distances euclidiennes calculées à partir de six mesures somatiques qui avaient été prises sur 60,140 chèvres adultes pour chaque race. La diversité génétique a été montrée par un dendrogramme bâti sur la matrice des distances de Nei obtenues des 201 marqueurs moléculaires AFLP, produits par 7 combinaisons de primers, sur 30 sujets pour chaque race. La décomposition de la variabilité génétique totale estimée par les données moléculaires a montré que la plus part de la variabilité est conservée parmi la population, tandis que seulement l,8,8% peut être imputé aux différences entre populations. Les données moléculaires et somatiques ont donné lieu à des distances qui ne sont pas corrélées et à des cluster avec une topologie nettement différente. La comparaison entre les deux approches permet d'avancer l'hypothèse que l'originalité somatique de la chèvre de la Val di Livo pourrait être due à des facteurs d'environnement et/ou à la pression de sélection plutôt qu'à des facteurs liés à l'évolution du genome. Au contraire ces derniers seraient responsables de l'originalité génétique de la race Orobica et confirmeraient des témoignages orals non documentés. Un choix objectif des ressources génétiques qui méritent d'être conservées pourra probablement se baser sur l'employ conjoint des marqueurs et de renseignements sur les caractères quantitatifs et sur les variantes alléliques des gènes qui ont une valeur adaptative. Diversität in fünf Ziegenpopulationen der lombardischen Alpen: Vergleich von Schätzungen auf der Basis morphologischer Eigenschaften und molekularer Marker Es wurden die phänotypische und genetische Variabilität innerhalb und zwischen Bionda dell'Adamello, Frisa, Orobica, Verzaschese und Val di Livo Ziegenpopulationen untersucht. Diese Populationen, mit Größen zwischen 1000 und 8000 Tieren, werden den größten Teil des Jahres auf Weiden der lombardischen Alpen gehalten. Die vier erstgenannten Populationen sind erst kürzlich standardisierte Rassen; gegenwärtig werden sie mit EU-Mitteln für die Erhaltung seltener Rassen, unterstützt. Auf der Basis des erkennbaren genetischen Profils muß die Rasse Val di Livo als eine Primärpopulation eingeordnet werden. Phänotypische Variabilität wurde auf der Basis von sechs Körpermaßen an 60,140 ausgewachsenen Ziegen je Rasse geschätzt, die genetische Variation wurde auf der Basis von 201 AFLP-Loci gemessen. Die Aufteilung der gesamten molekularen Varianz in Varianzkomponenten innerhalb und zwischen Populationen zeigt, daß der größte Teil der molekularen Variabilität innerhalb der Populationen auftritt, und nur 8,8% der Gesamtvarianz auf die Varianz zwischen den Populationen entfällt. Morphologische und molekulare Marker erzeugten unabhängige Distanzwerte und unterschiedliche upgma-Cluster. Es kann die Hypothese aufgestellt werden, daß die morphologische Einzigartigkeit der Val di Livo Ziege stärker auf Umwelteffekte und Selektionsdruck als auf eine unterschiedliche Herkunft oder genomische Evolution zurückzuführen ist. Dagegen scheint Orobica auf Genomebene von den anderen Rassen abzuweichen, was durch einen nicht dokumentierten süditalienischen Ursprung erklärt werden könnte. Eine objektive Bewertung von Prioritäten für Konservierungsmaßnahmen dürfte in Zukunft auf einen integrierten Gebrauch molekularer Marker, Informationen über quantitative Merkmale sowie der genetischen Variation bezüglich der Adaptationsfähigkeit basieren. [source] Phenotypic variability in myotonia congenitaMUSCLE AND NERVE, Issue 1 2005Eskild Colding-Jørgensen MDArticle first published online: 22 MAR 200 Abstract Myotonia congenita is a hereditary chloride channel disorder characterized by delayed relaxation of skeletal muscle (myotonia). It is caused by mutations in the skeletal muscle chloride channel gene CLCN1 on chromosome 7. The phenotypic spectrum of myotonia congenita ranges from mild myotonia disclosed only by clinical examination to severe and disabling myotonia with transient weakness and myopathy. The most severe phenotypes are seen in patients with two mutated alleles. Heterozygotes are often asymptomatic but for some mutations heterozygosity is sufficient to cause pronounced myotonia, although without weakness and myopathy. Thus, the phenotype depends on the mutation type to some extent, but this does not explain the fact that severity varies greatly between heterozygous family members and may even vary with time in the individual patient. In this review, existing knowledge about phenotypic variability is summarized, and the possible contributing factors are discussed. Muscle Nerve, 2005 [source] Phenotypic variability in the brains of a family with a prion disease characterized by a 144-base pair insertion in the prion protein geneNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 2 2003A. King The use of prion protein (PrP) immunohistochemistry in neuropathology has allowed identification of prion diseases with otherwise atypical histological features. The brains from family members with familial prion diseases can show marked histological variation. A histological and immunohistochemical study was performed on 10 brains of patients with a familial prion disease caused by a 144-base pair (bp) insertion in the prion protein gene. The histology from the cases showed variability in the severity of spongiform change and astrocytosis in both the cerebellum and the cerebrum. There was also variability in the density of microglial cells. The PrP immunohistochemistry revealed that in nine cases there was a similar patch-like deposition of PrP within the molecular layer of the cerebellum. Although in the cerebellum there did seem to be some correlation between the severity of spongiform change, astrocytosis and the density of microglial cells, there was no such correlation between any of these three parameters and the density of PrP staining. There was deposition of ,-amyloid precursor protein (,-APP) in the cerebellum, suggesting that disrupted axonal transport had a possible role in the evolution of the disease. The cases illustrate the histological variability that can occur in familial prion diseases despite similarity in PrP staining. They also reveal that the relationship between PrP deposition and cerebral or cerebellar damage might be complex. [source] 4125: Phenotypic variability in association with mutation in RDS/peripherinACTA OPHTHALMOLOGICA, Issue 2010GE HOLDER Purpose To report the clinical and electrophysiological findings associated with autosomal dominant maculopathy caused by mutations in Rds/peripherin. Methods Fifty three individuals with autosomal dominant macular dystrophy and a confirmed molecular diagnosis of Rds/peripherin mutation were ascertained between January 2002 and December 2008. International-standard pattern and full-field electroretinograms (PERG; ERG) were performed in 38 cases. Electro-oculograms (EOG) were performed in 25 cases. Results Fourteen different mutations were identified in the Rds/peripherin gene; 4 of which were novel. Twenty four (45%) patients had the common p.Arg172 Trp allele. The mean age at the time of first symptoms and at diagnosis was 35.0+/- 2.4 and 47.1 +/- 1.5 years old [SEM] respectively. Mean LogMAR visual acuity at presentation was 0.5+/- 0.08 [SEM]. Fundus phenotypes included central atrophy (19 cases), pattern dystrophy (10 cases), maculopathy with flecks (5 cases), and adult vitellifom dystrophy (4 cases). Pattern ERG P50 reduction was seen in 75 of 76 eyes; the majority having undetectable or residual responses, including some cases with preserved visual acuity. ERG ranged from normal to severe reduction in both cone and rod driven responses and were not predictable either from the fundus appearance or from the specific mutation in Rds/peripherin; on addition, marked intra-familial variation could be noted. Conclusion Mutations in the Rds/peripherin gene result in a wide variety of fundus and functional phenotypes. The same mutation can result in profoundly different phenotypes, even within family members. [source] PROP1 gene analysis in Portuguese patients with combined pituitary hormone deficiencyCLINICAL ENDOCRINOLOGY, Issue 4 2006Manuel C. Lemos Summary Objective, Mutations of the PROP1 gene lead to combined pituitary hormone deficiency (CPHD), which is characterized by a deficiency of GH, TSH, LH/FSH, PRL and, less frequently, ACTH. This study was undertaken to investigate the molecular defect in a cohort of patients with CPHD. Design, patients and measurements, A multicentric study involving 46 cases of CPHD (17 familial cases belonging to seven kindreds and 29 sporadic cases) selected on the basis of clinical and hormonal evidence of GH deficiency, central hypothyroidism and hypogonadotrophic hypogonadism, in the absence of an identified cause of hypopituitarism. Mutations of PROP1 were investigated by DNA sequencing. Clinical, hormonal and neuroradiological data were collected at each centre. Results,PROP1 mutations were identified in all familial cases: five kindreds presented a c. 301,302delAG mutation, one kindred presented a c. 358C , T (R120C) mutation and one presented a previously unreported initiation codon mutation, c. 2T , C. Of the 29 sporadic cases, only two (6·9%) presented PROP1 germline mutations (c. 301,302delAG, in both). Phenotypic variability was observed among patients with the same mutations, particularly the presence and age of onset of hypocortisolism, the levels of PRL and the results of pituitary imaging. One patient presented a sellar mass that persisted into adulthood. Conclusions, This is the first report of a mutation in the initiation codon of the PROP1 gene and this further expands the spectrum of known mutations responsible for CPHD. The low mutation frequency observed in sporadic cases may be due to the involvement of other unidentified acquired or genetic causes. [source] Phenotypic variability in isodicentric Y patients: study of nine casesCLINICAL GENETICS, Issue 2 2006M DesGroseilliers Isodicentric chromosomes are the most commonly reported aberrations of the human Y chromosome. As they are unstable during cell division and can generate various types of cell lines, most reported patients are chromosomal mosaics, generally including a 45,X cell line. Phenotypes depend on the location of the breakpoints as well as on the proportion of each cell line and vary from male to abnormal female or individual with ambiguous genitalia. Although phenotypic variability is known to also depend on the degree of mosaicism in the various tissues, gonads are rarely studied. We report nine cases of isodicentric Y chromosomes studied by conventional and molecular cytogenetic: three males, five females, and one individual with sexual ambiguity. Two males had a non-mosaic karyotype, while the third male was a mosaic with a predominant 46,XY cell line. Three of the females had a major 45,X cell line, while the last two females and the patient with ambiguous genitalia had a major 46,X,idic(Y) cell line. Analyses of gonadal tissues from the individual with sexual ambiguity and of three of the five female patients gave results concordant with their phenotype, allowing us to better understand the sexual differentiation of these patients. [source] Embryonic holoprosencephaly: pathology and phenotypic variabilityCONGENITAL ANOMALIES, Issue 4 2006Shigehito Yamada ABSTRACT Holoprosencephaly (HPE) is one of the major brain anomalies caused by the failure of cleavage of the prosencephalon during the early stage of development. Over 200 cases of HPE in the Kyoto Collection of Human Embryos were observed grossly and histologically, with special emphasis on the anomalies of the brain, face and eye. The facial anomalies of HPE human embryos after Carnegie stage (CS) 18 could be classified into cyclopia, synophthalmia, ethmocephaly, cebocephaly, and premaxillary agenesis, similarly as the classical classification for postnatal cases. On the other hand, HPE embryos at CS 13,17 showed some characteristic facies which are different from those in older embryos. In the present paper, pathology and phenotypic variability in HPE embryos were discussed from the embryopathological point of view. Recently, the molecular mechanism of HPE has been clarified by the techniques of gene manipulation, and various HPE genes have been identified by gene analysis of familial HPE cases. HPE is one of the major CNS anomalies which have been extensively studied and provides a clue to the mechanisms of normal and abnormal development of craniofacial structures. [source] Spatial Autocorrelation Analysis and the Identification of Operational Units for Conservation in Continuous PopulationsCONSERVATION BIOLOGY, Issue 4 2002José Alexandre Felizola Diniz-Filho We show that spatial autocorrelation analysis, applied to phenotypic or molecular data, can be used to describe the geographic structure and therefore can help define optimum strategies for conserving genetic variability within species. We propose that the intercept of a spatial correlogram can be an indication of the minimum distance between samples that can conserve and assess genetic diversity with maximum efficiency at lower costs. This parameter can be used both to define units and to establish sampling strategies for conservation programs. We illustrate the utility of this approach by autocorrelation analyses applied to three data sets: isozyme variability among Eugenia dysenterica populations in Brazilian Cerrado and within populations of Adenophora glandiflora in Korea, and microsatellite variation among Ursus arctos populations in North America. Our results suggest that the intercept of spatial correlograms is a useful parameter for establishing operational units for intraspecific conservation in continuous populations, based on overall genetic or phenotypic variability, by defining the minimum geographic distance at which samples are independent. Resumen: A pesar de los avances recientes en la identificación de la estructura genética poblacional mediante la tecnología de marcadores moleculares, la definición de las unidades intraespecíficas para la conservación es aún problemática. Esto sucede particularmente cuando la variación genética y fenotípica se encuentra distribuida de manera continua en un espacio geográfico. Demostramos que el análisis de autocorrelación espacial, aplicado a los datos fenotípicos o moleculares puede ser usado para describir la estructura geográfica y, por lo tanto, puede ayudar a definir estrategias óptimas para la conservación de la variabilidad genética en las especies. Proponemos que el intercepto de un correlograma espacial puede ser un indicador de la distancia mínima entre muestras que pueden conservar y evaluar la diversidad genética con mayor eficiencia a un costo más bajo. Este parámetro puede ser usado tanto para definir unidades como para establecer estrategias de muestreo para los programas de conservación. Ejemplificamos la utilidad de este método mediante la aplicación de análisis de autocorrelación a tres grupos de datos: variabilidad de isozomas entre poblaciones de Adenophora dysenterica en el cerrado brasileño, dentro de poblaciones de Adenophora glandiflora en Korea y variación microsatélite entre poblaciones de Ursus arctos en América del Norte. Nuestros resultados sugieren que el intercepto de los correlogramas espaciales son un parámetro útil que puede establecer unidades operacionales para conservación intraespecífica en poblaciones continuas, en base a la variabilidad general genética o fenótipica, al definir la distancia geográfica mínima a la cual las muestras son independientes. [source] Penetrance estimation of TTR familial amyloid polyneuropathy (type I) in Brazilian familiesEUROPEAN JOURNAL OF NEUROLOGY, Issue 3 2009M. A. C. Saporta Background and purpose:, Familial amyloid polyneuropathy (FAP) type I is a severe autosomal dominant inherited neuropathy associated with mutations in the transthyretin (TTR) gene. Significant phenotypic variability is seen amongst families with distinct geographic origin, especially regarding penetrance and age of onset. The aim of this study was to estimate the penetrance of FAP in Brazilian families. Methods:, Twenty-two distinct families were ascertained through genetically confirmed index cases and included in this study. Genealogical and clinical data were obtained from a total of 623 individuals, including 126 affected by FAP. In 15 families, TTR genotyping was performed in all available relatives (n = 86), after informed written consent. Seven families did not consent for genetic testing, but agreed to provide clinical and genealogical data. Penetrance was estimated using a previously described method based on survival analysis and corrected for ascertainment bias. Results:, Mean age of onset in our sample was 34.5 years, with a significant earlier onset in males (31.1 vs. 35.9, P < 0.0001). The penetrance of FAP in our sample was estimated as 83% (95% CI: 66,99) after 60 years. Conclusion:, Our results provide new information on FAP in Brazilian patients and may be helpful in the genetic counseling of this population. [source] Disruption of the palatal rugae pattern in Tabby (eda) mutant miceEUROPEAN JOURNAL OF ORAL SCIENCES, Issue 6 2007Cyril Charles The eda mouse gene is linked with anomalies of ectodermal derivatives, such as hair, glands, and teeth. The palatal rugae (oral mucosa foldings on the hard palate) are also ectodermal derivatives. Therefore, we searched for and compared palatal rugae anomalies of Tabby mice bearing a mutation in the eda gene with their wild-type counterparts. We compared the number and shape of palatal rugae in 179 mutant and 102 wild-type mice from four different stocks of Tabby mice. Palatal rugae anomalies were documented at a low frequency in wild-type mice of different backgrounds, which may reflect a lack of robustness of palatal rugae development. However, the proportion of anomalies observed in the C57BL/6J background makes us recommend avoiding its use in further palate studies. We showed statistically that the phenotypic variability seen in wild-type animals is further increased in Tabby mutants. The anomalies mainly included various forms of reduction, with rugae IV,VI being more frequently affected. Those rugae were shortened, dotted or absent (mainly ruga V). By analogy to the role played by eda in other ectodermal derivatives, we propose that it might play a role in defining the pattern of the palatal rugae. [source] A novel nonsense mutation in PAX9 is associated with marked variability in number of missing teethEUROPEAN JOURNAL OF ORAL SCIENCES, Issue 4 2007Lars Hansen Tooth development is under strict genetic control. During the last decade, studies in molecular genetics have led to the identification of gene defects causing the congenital absence of permanent teeth. Analyses of PAX9 and MSX1 in nine families with hypodontia and oligodontia revealed one new PAX9 mutation. A LOD score of Z = 1.8 (, = 0.0) was obtained for D14S75 close to PAX9 in one three-generation family, and sequencing of the gene identified the nonsense mutation c.433C>T. The mutation results in a truncated PAX9 protein containing the paired domain region as a result of the Q145X stop mutation. The family showed a marked phenotypic variability in the number of missing teeth, ranging from 2 to 15 missing teeth. The highest frequency of missing teeth was found for second molars followed by second premolars. [source] Molecular genetics of pseudoxanthoma elasticumEXPERIMENTAL DERMATOLOGY, Issue 4 2001F. Ringpfeil Abstract: Pseudoxanthoma elasticum (PXE), a systemic heritable connective tissue disorder, is characterized by progressive calcification of elastic structures in the skin, the eyes and the cardiovascular system, with considerable intra- and interfamilial phenotypic variability. Recently, underlying genetic defects have been identified in the ABCC6 gene, which resides on the chromosomal locus 16p13.1 and encodes the MRP6 protein, a member of the ATP-binding cassette (ABC) family of proteins. The affected individuals are homozygous or compound heterozygous for a spectrum of genetic lesions, including nonsense and missense mutations, or deletions and splice-site alterations, confirming the autosomal recessive nature of this condition. Analysis of the deduced primary sequence suggests that MRP6 is a transmembrane transporter, but its function has not been delineated yet. Surprisingly, however, MRP6 is expressed primarily, if not exclusively, in the liver and the kidneys, suggesting that PXE may be a primary metabolic disorder with secondary involvement of elastic fibers. Identification of mutations in the ABCC6 gene in PXE provides a means for prenatal and presymptomatic testing in families at risk for recurrence. DNA-based analyses will also identify heterozygous carriers who may be at risk for development of limited manifestations of the disease as a result of compounding genetic factors and/or environmental modifiers. [source] Bile duct proliferation in Jag1/fringe heterozygous mice identifies candidate modifiers of the alagille syndrome hepatic phenotype,HEPATOLOGY, Issue 6 2008Matthew J. Ryan Alagille syndrome (AGS) is a heterogeneous developmental disorder associated with bile duct paucity and various organ anomalies. The syndrome is caused by mutations in JAG1, which encodes a ligand in the Notch signaling pathway, in the majority of cases and mutations in the NOTCH2 receptor gene in less than 1% of patients. Although a wide array of JAG1 mutations have been identified in the AGS population, these mutational variants have not accounted for the wide phenotypic variability observed in patients with this syndrome. The Fringe genes encode glycosyltransferases, which modify Notch and alter ligand-receptor affinity. In this study, we analyzed double heterozygous mouse models to examine the Fringe genes as potential modifiers of the Notch-mediated hepatic phenotype observed in AGS. We generated mice that were haploinsufficient for both Jag1 and one of three paralogous Fringe genes: Lunatic (Lfng), Radical (Rfng), and Manic (Mfng). Adult Jag1+/,Lfng+/, and Jag1+/,Rfng+/, mouse livers exhibited widespread bile duct proliferation beginning at 5 weeks of age and persisting up to 1 year. The Jag1+/,Mfng+/, livers showed a subtle, yet significant increase in bile duct numbers and bile duct to portal tract ratios. These abnormalities were not observed in the newborn period. Despite the portal tract expansion by bile ducts, fibrosis was not increased and epithelial to mesenchymal transition was not shown in the affected portal tracts. Conclusion: Mice heterozygous for mutations in Jag1 and the Fringe genes display striking bile duct proliferation, which is not apparent at birth. These findings suggest that the Fringe genes may regulate postnatal bile duct growth and remodeling, and serve as candidate modifiers of the hepatic phenotype in AGS. (HEPATOLOGY 2008;48:1989,1997.) [source] Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel-Gruber syndrome,HUMAN MUTATION, Issue 1 2008Valeska Frank Abstract Meckel-Gruber syndrome (MKS) is an autosomal recessive, lethal multisystemic disorder characterized by meningooccipital encephalocele, cystic kidney dysplasia, hepatobiliary ductal plate malformation, and postaxial polydactyly. Recently, genes for MKS1 and MKS3 were identified, putting MKS on the list of ciliary disorders (ciliopathies). By positional cloning in a distantly related multiplex family, we mapped a novel locus for MKS to a 3-Mb interval on 12q21. Sequencing of the CEP290 gene located in the minimal critical region showed a homozygous 1-bp deletion supposed to lead to loss of function of the encoded centrosomal protein CEP290/nephrocystin-6. CEP290 is thought to be involved in chromosome segregation and localizes to cilia, centrosomes, and the nucleus. Subsequent analysis of another consanguineous multiplex family revealed homozygous haplotypes and the same frameshift mutation. Our findings add to the increasing body of evidence that ciliopathies can cause a broad spectrum of disease phenotypes, and pleiotropic effects of CEP290 mutations range from single organ involvement with isolated Leber congenital amaurosis to Joubert syndrome and lethal early embryonic multisystemic malformations in Meckel-Gruber syndrome. We compiled clinical and genetic data of all patients with CEP290 mutations described so far. No clear-cut genotype,phenotype correlations were apparent as almost all mutations are nonsense, frameshift, or splice-site changes and scattered throughout the gene irrespective of the patients' phenotypes. Conclusively, other factors than the type and location of CEP290 mutations may underlie phenotypic variability. Hum Mutat 29(1), 45,52, 2008. © 2007 Wiley-Liss, Inc. [source] Hydrodynamic sorting in a coastal marine skeletal assemblageINTERNATIONAL JOURNAL OF OSTEOARCHAEOLOGY, Issue 4 2002*Article first published online: 9 AUG 200, Christopher M. Stojanowski Abstract In this paper I evaluate the effects of wave and tidal erosion on element-specific measures of phenotypic variability. Previous research has found a high correlation between skeletal weight, shape, and density and the transport potential of an element exposed to hydrodynamic forces. However, no previous studies have attempted to address the issue of within-element sorting based on selective removal of only the smallest members of a given element class. I evaluate this hypothesis using a human skeletal sample from Bird Island (8DI52) located in Dixie County, Florida. This sample comprises two components, an eroded sample that was exposed during severe storm and tidal activity, and an uneroded sample excavated from primary context. The measurement-specific means for the subcomponents were compared using Student's t and Wilcoxon tests and variability differences were evaluated based on standard deviations, coefficients of variation, and maximum/minimum indices. The data included maxillary and mandibular tooth dimensions and postcranial metrics. No evidence for selective winnowing based on within-element size was found in this data set. Copyright © 2002 John Wiley & Sons, Ltd. [source] Morphological variability of the Asiatic cyprinid, topmouth gudgeon Pseudorasbora parva, in its introduced European rangeJOURNAL OF FISH BIOLOGY, Issue 1 2009E. Záhorská To assess the spatial variability in external morphology of non-native populations of topmouth gudgeon Pseudorasbora parva within an ontogenetic context, triple regression analysis (distance-based measurements) was applied to data from eight European populations (two Slovak, four Romanian, one English and one French). The data from Slovakia were also subjected to geometrical analysis (co-ordinates-based measurements) to obtain a more complex picture of the species' overall morphology. Great phenotypic variability was observed, being expressed not only in the formation of different definite phenotypes but also in the manner by which the phenotypes are achieved. Thus, both the definite phenotype and the patterns of development in invasive P. parva may be highly influenced by environmental conditions. Such great morphological (phenotypic) variability is likely to be one of the attributes that make this species such a successful invader. [source] Variable phenotype of Alzheimer's disease with spastic paraparesisJOURNAL OF NEUROCHEMISTRY, Issue 3 2008Helena Karlstrom Abstract Pedigrees with familial Alzheimer's disease (AD) show considerable phenotypic variability. Spastic paraparesis (SP), or progressive spasticity of the lower limbs is frequently hereditary and exists either as uncomplicated (paraparesis alone) or complicated (paraparesis and other neurological features) disease subtypes. In some AD families, with presenilin-1 (PSEN1) mutations, affected individuals also have SP. These PSEN1 AD pedigrees frequently have a distinctive and variant neuropathology, namely large, non-cored plaques without neuritic dystrophy called cotton wool plaques (CWP). The PSEN1 AD mutations giving rise to CWP produce unusually high levels of the amyloid , peptide (A,) ending at position 42 or 43, and the main component of CWP is amino-terminally truncated forms of amyloid , peptide starting after the alternative ,-secretase cleavage site at position 11. This suggests a molecular basis for the formation of CWP and an association with both SP and AD. The SP phenotype in some PSEN1 AD pedigrees also appears to be associated with a delayed onset of dementia compared with affected individuals who present with dementia only, suggesting the existence of a protective factor in some individuals with SP. Variations in neuropathology and neurological symptoms in PSEN1 AD raise the prospect that modifier genes may underlie this phenotypic heterogeneity. [source] Pituitary Transcription Factors: From Congenital Deficiencies to Gene TherapyJOURNAL OF NEUROENDOCRINOLOGY, Issue 9 2006M. H. Quentien Despite the existence of interspecies phenotypic variability, animal models have yielded valuable insights into human pituitary diseases. Studies on Snell and Jackson mice known to have growth hormone, prolactin and thyroid-stimulating hormone deficiencies involving the hypoplastic pituitary gland have led to identifying alterations of the pituitary specific POU homeodomain Pit-1 transcription factor gene. The human phenotype associated with rare mutations in this gene was found to be similar to that of these mice mutants. Terminal differentiation of lactotroph cells and direct regulation of the prolactin gene both require interactions between Pit-1 and cell type specific partners, including panpituitary transcriptional regulators such as Pitx1 and Pitx2. Synergistic activation of the prolactin promoter by Pitx factors and Pit-1 is involved not only in basal condition, but also in responsiveness to forskolin, thyrotrophin-releasing-hormone and epidermal growth factor. In corticotroph cells, Pitx1 interacts with Tpit. Tpit mutations have turned out to be the main molecular cause of neonatal isolated adrenocorticotrophin deficiency. This finding supports the idea that Tpit plays an essential role in the differentiation of the pro-opiomelanocortin pituitary lineage. The effects of Pit-1 are not restricted to hormone gene regulation because this factor also contributes to cell division and protects the cell from programmed cell death. Lentiviral vectors expressing a Pit-1 dominant negative mutant induced time- and dose-dependent cell death in somatotroph and lactotroph adenomas in vitro. Gene transfer by lentiviral vectors should provide a promising step towards developing an efficient specific therapeutic approach by which a gene therapy programme for treating human pituitary adenomas could be based. [source] GLOBAL SYSTEMATIC AND PHYLOGENETIC ANALYSIS OF SARGASSUM IN THE GULF OF MEXICO, CARIBBEAN AND PACIFIC BASINJOURNAL OF PHYCOLOGY, Issue 2000N. Phillips Sargassum is one of the most species-rich genera in the brown algae with over 400 described species worldwide. The bulk of these species occurs in Pacific-Indian ocean waters with only a small portion found on the Atlantic side of the Isthmus of Panama. Sargassum also has one of the most subdivided and complex taxonomic systems used within the algae. Systematic distinctions within the genus are further complicated by high rates of phenotypic variability in several key morphological characters. Molecular analyses in such systems should allow testing of systematic concepts while providing insights into speciation and evolutionary patterns. Global molecular phylogenetic analyses using both conserved and variable regions of the Rubisco operon (rbcL and rbcL-IGS-rbcS) were performed with species from the Gulf of Mexico, Caribbean, and Pacific basin. Results confirm earlier analyses based on rbcL-IGS- rbcS from Pacific species at the subgeneric and sectional level while providing additional insights into the systematics and phylogenetics on a global scale. For example, species east of the Isthmus of Panama form a distinct well-resolved clade within the tropical subgenus. This result in sharp contrast to traditional systematic treatments but provides a window into the evolutionary history of this genus in the Pacific and Atlantic Ocean basins and a possible means to time speciation events. [source] Bayesian inference of evolutionary history from chloroplast microsatellites in the cosmopolitan weed Capsella bursa - pastoris (Brassicaceae)MOLECULAR ECOLOGY, Issue 14 2005ALF CEPLITIS Abstract Besides showing an extraordinary degree of phenotypic variability, Capsella bursa-pastoris (Brassicaceae) is also one of the world's most common plant species and a serious weed in many countries. We have employed a coalescent-based Bayesian analysis of chloroplast microsatellite data to infer demographic and evolutionary parameters of this species. Two different demographic models applied to data from seven chloroplast microsatellite loci among 59 accessions show that the effective population size of C. bursa-pastoris is very small indicating a rapid expansion of the species, a result that is in accordance with fossil and historical data. Against this background, analysis of flowering time variation among accessions suggests that ecotypic differentiation in flowering time has occurred recently in the species' history. Finally, our results also indicate that mononucleotide repeat loci in the chloroplast genome can deteriorate in relatively short periods of evolutionary time. [source] Prevalence of THAP1 sequence variants in German patients with primary dystonia,MOVEMENT DISORDERS, Issue 12 2010Anne S. Söhn PhD Abstract Primary dystonias are a clinically and genetically heterogeneous group of movement disorders, but only for two of them, i.e., dystonia 1 and dystonia 6, the disease causing gene has been identified. Dystonia 1 is characterized by an early onset and is caused by a mutation in the TOR1A gene. Only recently, mutations in THAP1 have been shown to be the cause of DYT6 dystonia. We analyzed 610 patients with various forms of dystonia for sequence variants in the THAP1 gene by means of high resolution melting to delineate the prevalence of sequence variants and phenotypic variability. We identified seven sequence variants in patients and one sequence variant in a control. The sequence variants were not detected in 537 healthy controls. Four patients present with generalized dystonia with speech involvement of early onset, another three patients suffered exclusively from cervical dystonia of adult onset. These findings suggest that THAP1 sequence variations seem to be associated with different ages of onset and distribution of symptoms. Consequently, the phenotypic spectrum might be broader than previously assumed. © 2010 Movement Disorder Society [source] Phenotypic variability in myotonia congenitaMUSCLE AND NERVE, Issue 1 2005Eskild Colding-Jørgensen MDArticle first published online: 22 MAR 200 Abstract Myotonia congenita is a hereditary chloride channel disorder characterized by delayed relaxation of skeletal muscle (myotonia). It is caused by mutations in the skeletal muscle chloride channel gene CLCN1 on chromosome 7. The phenotypic spectrum of myotonia congenita ranges from mild myotonia disclosed only by clinical examination to severe and disabling myotonia with transient weakness and myopathy. The most severe phenotypes are seen in patients with two mutated alleles. Heterozygotes are often asymptomatic but for some mutations heterozygosity is sufficient to cause pronounced myotonia, although without weakness and myopathy. Thus, the phenotype depends on the mutation type to some extent, but this does not explain the fact that severity varies greatly between heterozygous family members and may even vary with time in the individual patient. In this review, existing knowledge about phenotypic variability is summarized, and the possible contributing factors are discussed. Muscle Nerve, 2005 [source] UGT1A1 promoter polymorphisms and the development of hyperbilirubinemia and gallbladder disease in children with sickle cell anemiaAMERICAN JOURNAL OF HEMATOLOGY, Issue 10 2008Shannon L. Carpenter Genetic modifiers contribute to phenotypic variability in patients with sickle cell anemia (SCA). The influence of the bilirubin UDP-glucuronosyltransferase (UGT) 1A1 (TA)nTAA promoter polymorphism on bilirubin levels and gallbladder disease in SCA was examined using prospectively collected data from the Cooperative Study of Sickle Cell Disease. A total of 324 children with HbSS (median age 6.9 years) had UGT1A1 genotyping; 243 (75%) had common (TA)6 or (TA)7 alleles, whereas 81 (25.0%) had variant (TA)5 or (TA)8 alleles. The UGT1A1 genotype significantly influenced average bilirubin levels for the common alleles: 6/6 genotype = 2.36 ± 1.13 mg/dL, 6/7 genotype = 2.90 ± 1.54 mg/dL, and 7/7 genotype = 4.24 ± 2.11 mg/dL (P < 0.0001). Thirty-nine percent of children with the 7/7 genotype had documented gallbladder disease, compared with 18.2% with the 6/7 genotype and only 9.9% with the wildtype 6/6 UGT1A1 genotype (P = 0.001). To analyze the (TA)5 and (TA)8 variant alleles, three groups were generated, showing increasing bilirubin levels with increasing TA repeats and age. Group 3 (genotypes 6/8, 7/7, and 7/8) had a significantly greater rate of bilirubin change than Groups 1 (genotypes 5/6, 5/7, and 6/6) or 2 (genotype 6/7). These results validate previous smaller studies and confirm that the UGT1A1 promoter polymorphism exerts a powerful influence on bilirubin levels and the development of gallbladder disease in children with SCA. UGT1A1 genotyping should be considered as a screening tool for predicting children most likely to develop gallbladder disease at a young age. Am. J. Hematol., 2008. © 2008 Wiley-Liss, Inc. [source] Phenotypic approaches for understanding patterns of intracemetery biological variationAMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY, Issue S43 2006Christopher M. Stojanowski Abstract This paper reviews studies of phenotypic inheritance and microevolutionary processes in archaeological populations using data on cranial and dental phenotypic variation, often referred to as paleogenetics or biodistance analysis. The estimation of biological distances between populations, or among individuals within populations, is one component of bioarchaeological research on past populations. In this overview, five approaches that focus on morphological variation within cemeteries are summarized: kinship and cemetery structure analysis, postmarital residence analysis, sample aggregate phenotypic variability, temporal microchronology, and age-structured phenotypic variation. Previous research, theoretical justifications, and methods are outlined for each topic. Case studies are presented that illustrate these theoretical and methodological bases, as well as demonstrate the kinds of inferences possible using these approaches. Kinship and cemetery structure analysis seeks to identify the members of family groups within larger cemeteries or determine whether cemeteries were kin-structured. Analysis of sex-specific phenotypic variation allows estimation of postmarital residence practices, which is important for understanding other aspects of prehistoric social organization. Analysis of aggregate phenotypic variability can be used to infer site formation processes or cemetery catchment area. The study of temporal microchronologies can be used to evaluate provisional archaeological chronologies or study microevolutionary processes such as adaptive selection or changing patterns of gene flow. Finally, age-structured phenotypic variation can be reflective of selection processes within populations or it can be used as a measure of morbidity, growth arrest, and early mortality within past populations. Use of phenotypic data as a genotypic proxy is theoretically sound, even at small scales of analysis. Yrbk Phys Anthropol 49:49,88, 2006. © 2006 Wiley-Liss, Inc. [source] Indigenous domestic breeds as reservoirs of genetic diversity: the Argentinean Creole cattleANIMAL GENETICS, Issue 5 2001G. Giovambattista Contrary to highly selected commercial breeds, indigenous domestic breeds are composed of semi-wild or feral populations subjected to reduced levels of artificial selection. As a consequence, many of these breeds have become locally adapted to a wide range of environments, showing high levels of phenotypic variability and increased fitness under natural conditions. Genetic analyses of three loci associated with milk production (,S1 -casein, , -casein and prolactin) and the locus BoLA-DRB3 of the major histocompatibility complex indicated that the Argentinean Creole cattle (ACC), an indigenous breed from South America, maintains high levels of genetic diversity and population structure. In contrast to the commercial Holstein breed, the ACC showed considerable variation in heterozygosity (He) and allelic diversity (A) across populations. As expected, bi-allelic markers showed extensive variation in He whereas the highly polymorphic BoLA-DRB3 showed substantial variation in A, with individual populations having 39,74% of the total number of alleles characterized for the breed. An analysis of molecular variance (AMOVA) of nine populations throughout the distribution range of the ACC revealed that 91.9,94.7% of the total observed variance was explained by differences within populations whereas 5.3,8.1% was the result of differences among populations. In addition, the ACC breed consistently showed higher levels of genetic differentiation among populations than Holstein. Results from this study emphasize the importance of population genetic structure within domestic breeds as an essential component of genetic diversity and suggest that indigenous breeds may be considered important reservoirs of genetic diversity for commercial domestic species. [source] Leukocyte cDNA Analysis of NSD1 Derived from Confirmed Sotos Syndrome PatientsANNALS OF HUMAN GENETICS, Issue 6 2007M. Duno Summary Background: Haploinsufficiency of the NSD1 gene leads to Sotos syndrome (Sos), which is characterised by excessive growth, especially during childhood, distinct craniofacial features and variable degree of mental impairment. A wide spectrum of NSD1 mutations have been described in Sos patients, ranging from more than 100 different single nucleotide changes, to partial gene deletions, and to microdeletions of various sizes comprising the entire NSD1 locus. Objective: To investigate the NSD1 cDNA sequence in genetically confirmed Sos patients harbouring truncating and missense mutations. Method: Total RNA was isolated from a 250 ,l standard EDTA blood sample from nine genetically verified Sos patients, and subsequent reverse-transcribed into cDNA followed by PCR and direct sequencing of specific NSD1 cDNA sequences. Results: All nine mutations, including missense, nonsense and whole exon deletions, previously identified in genomic DNA, could confidently be detected in cDNA. Several NSD1 transcript splice variants were detected. Conclusion: Despite the fact that Sos is caused by haploinsufficiency, NSD1 transcripts containing nonsense and frame shift mutations can be detected in leukocyte-derived cDNA. The possibility therefore exists that certain NSD1 mutations are expressed and contribute to the phenotypic variability of Sos. NSD1 cDNA analysis is likely to enhance mutation detection in Sos patients. [source] The Impact of BRCA1 on Spina Bifida Meningomyelocele LesionsANNALS OF HUMAN GENETICS, Issue 6 2007Terri M. King Summary We examined the BRCA1 gene in 268 patients, and their parents, with a specific diagnosis of spina bifida meningomyelocele (SBMM). We genotyped two intragenic microsatellite markers (BRCA1 D17S1323, BRCA1 D17S1322) and 2 single nucleotide polymorphisms (A1186G, A4956G) in our patients. Transmission disequilibrium testing (TDT) showed significant association with A4956G, but not with A1186G. Extended TDT demonstrated over-transmission of the 17GT allele in BRCA1 D17S1323 and the 14GTT allele in BRCA1 D17S1322, and under-transmission of the 20GT allele in BRCA1 D17S1323 and the 16GTT allele in BRCA1 D17S1322. Our data included location of the rostral edge of the lesion. Individuals homozygous for the 17GT allele for BRCA1 D17S1323 were more likely to have SB lesions located caudally, while heterozygotes with the 17GT allele for BRCA1 D17S1323 had a more rostral lesion. Individuals heterozygous for the 16GTT allele of BRCA1 D17S1322 were more likely to have rostral lesions. We measured gene expression in CEPH members and demonstrated differential expression levels of BRCA1 associated with these polymorphisms. Integrating our data with HapMap findings showed that the polymorphic markers are associated with distinct haplotypes. We conclude that the BRCA1 gene is associated with SBMM and participates in the phenotypic variability seen in SBMM. [source] Clinical features and neuropathology of autosomal dominant spinocerebellar ataxia (SCA17)ANNALS OF NEUROLOGY, Issue 3 2003Arndt Rolfs MD Autosomal dominant spinocerebellar ataxias (SCAs) are a group of neurodegenerative disorders clinically characterized by late-onset ataxia and variable other manifestations. Genetically and clinically, SCA is highly heterogeneous. Recently, CAG repeat expansions in the gene encoding TATA-binding protein (TBP) have been found in a new form of SCA, which has been designated SCA17. To estimate the frequency of SCA17 among white SCA patients and to define the phenotypic variability, we determined the frequency of SCA17 in a large sample of 1,318 SCA patients. In total, 15 patients in four autosomal dominant SCA families had CAG/CAA repeat expansions in the TBP gene ranging from 45 to 54 repeats. The clinical features of our SCA17 patients differ from other SCA types by manifesting with psychiatric abnormalities and dementia. The neuropathology of SCA17 can be classified as a "pure cerebellar" or "cerebello-olivary" form of ataxia. However, intranuclear neuronal inclusion bodies with immunoreactivity to anti-TBP and antipolyglutamine were much more widely distributed throughout the brain gray matter than in other SCAs. Based on clinical and genetic data, we conclude that SCA17 is rare among white SCA patients. SCA17 should be considered in sporadic and familial cases of ataxia with accompanying psychiatric symptoms and dementia. [source] Evolutionary genetics of genital size and lateral asymmetry in the earwig Euborellia plebeja (Dermaptera: Anisolabididae)BIOLOGICAL JOURNAL OF THE LINNEAN SOCIETY, Issue 1 2010YOSHITAKA KAMIMURA Male genitalia show several evolutionary characteristics, including rapid morphological divergence between closely related species and low within-species phenotypic variability. In addition, genital asymmetry is widespread despite the essentially bilaterally symmetric external morphology of insects. Several hypotheses, such as sexual selection and lock-and-key hypotheses, have been proposed to explain these characteristics of genital evolution. Although these hypotheses provide different predictions about the genetic basis of variation in genitalia, detailed quantitative genetic studies have been conducted in only three insect taxa: heteropterans, dung beetles (Scarabaeidae), and drosophilid flies. For an anisolabidid earwig, Euborellia plebeja, characterized by paired elongated intromittent organs, we estimated the heritabilities and genetic correlations of genital laterality, size of genitalia, and body size. No statistically significant additive genetic, dominance, maternal, or common environmental effects were detected for genital laterality (readiness to use either the left or the right intromittent organ). This result lends further support to the general rule that the direction of antisymmetric variations is randomly determined by non-genetic factors. Irrespective of the restricted phenotypic variation in genitalia compared with body size (allometric slope < 1), as observed in previous studies for other insects, these two traits showed a similar level of genetic variation, measured as the narrow sense heritability (h2) and the coefficient of additive genetic variation (CVA). Comparison suggests the causes of interspecific differences in genetic variability/correlation structures were developmental processes (holo- or hemimetabolous) and/or mode of sexual selection. © 2010 The Linnean Society of London, Biological Journal of the Linnean Society, 2010, 101, 103,112. [source] | |||||||||||||||||||||||||||||||