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Heterozygous Missense Mutation (heterozygous + missense_mutation)

Distribution by Scientific Domains

Medical Sciences	81%

Distribution within Medical Sciences

Neurology	55%
Dermatology	22%

Selected Abstracts

Novel keratin 16 mutations and protein expression studies in pachyonychia congenita type 1 and focal palmoplantar keratoderma

EXPERIMENTAL DERMATOLOGY, Issue 3 2000
F. J. D. Smith
Abstract: Pachyonychia congenita type 1 (PC-1) is an autosomal dominant ectodermal dysplasia characterized by nail dystrophy, focal non-epidermolytic palmoplantar keratoderma (FNEPPK) and oral lesions. We have previously shown that mutations in keratin 16 (K16) cause fragility of specific epithelia resulting in phenotypes of PC-1 or FNEPPK alone. Here, we report 2 novel mutations in K16 causing distinct phenotypes. A heterozygous missense mutation (L124R) was detected in a kindred with PC-1. In a family where mild FNEPPK was the only phenotype, a 23 bp deletion and a separate 1 bp deletion downstream were found in exon 6: [1244,1266del; 1270delG]. At the protein level, these mutations remove 8 residues and substitute 2 residues in the helix termination motif (HTM) of the K16 polypeptide. The HTM sequence is conserved in all known intermediate filament proteins and for convenience, this complex mutation was designated ,HTM. Transient expression of K16 cDNAs carrying either the L124R or the ,HTM mutation in epithelial cell line PtK2 produced aggregation of the keratin cytoskeleton. However, the aggregates observed with the ,HTM mutation were morphologically different and appeared to be less disruptive to the endogenous cytoskeleton. Therefore, loss of the HTM sequence may render this mutant K16 less capable of contributing to filament assembly and decrease its dominant-negative effect, resulting in the milder FNEPPK phenotype. [source]

Dysregulated BMP Signaling and Enhanced Osteogenic Differentiation of Connective Tissue Progenitor Cells From Patients With Fibrodysplasia Ossificans Progressiva (FOP),

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 3 2008
Paul C Billings
Abstract The study of FOP, a disabling genetic disorder of progressive heterotopic ossification, is hampered by the lack of readily available connective tissue progenitor cells. We isolated such cells from discarded primary teeth of patients with FOP and controls and discovered dysregulation of BMP signaling and rapid osteoblast differentiation in FOP cells compared with control cells. Introduction: Fibrodysplasia ossificans progressiva (FOP), the most disabling condition of progressive heterotopic ossification in humans, is caused by a recurrent heterozygous missense mutation in activin receptor IA (ACVR1), a bone morphogenetic protein (BMP) type I receptor, in all classically affected individuals. A comprehensive understanding of FOP has been limited, in part, by a lack of readily available connective tissue progenitor cells in which to study the molecular pathology of this disorder. Materials and Methods: We derived connective tissue progenitor cells from discarded primary teeth (SHED cells) of patients with FOP and controls and examined BMP signaling and osteogenic differentiation in these cells. Results: SHED cells transmitted BMP signals through both the SMAD and p38 mitogen-activated protein kinase (MAPK) pathways and responded to BMP4 treatment by inducing BMP responsive genes. FOP cells showed ligand-independent BMP signaling and ligand-dependent hyper-responsiveness to BMP stimulation. Furthermore, FOP cells showed more rapid differentiation to an osteogenic phenotype than control cells. Conclusions: This is the first study of BMP signaling and osteogenic differentiation in connective tissue progenitor cells from patients with FOP. Our data strongly support both basal and ligand-stimulated dysregulation of BMP signaling consistent with in silico studies of the mutant ACVR1 receptor in this condition. This study substantially extends our understanding of dysregulated BMP signaling in a progenitor cell population relevant to the pathogenesis of this catastrophic disorder of progressive ectopic ossification. [source]

A recurrent ITGA9 missense mutation in human fetuses with severe chylothorax: possible correlation with poor response to fetal therapy

PRENATAL DIAGNOSIS, Issue 11 2008
Gwo-Chin Ma
Abstract Objectives To assess the possible correlations between the reported candidate genes (VEGFR3, FOXC2, ITGA9 and ITGB1) and the clinical response in fetuses with severe congenital chylothorax (CC) treated by prenatal OK-432 pleurodesis. Methods We studied 12 unrelated fetuses with severe CC, receiving fetal therapy by OK-432 pleurodesis. Genotyping of the candidate genes and the clinical parameters of these 12 fetuses were investigated. Additional 96 control individuals were enrolled to evaluate the possible polymorphisms at these candidate genes in population. Results A recurrent heterozygous missense mutation (c.1210G > A, p.G404S) was identified in the beta-propeller domain of integrin ,9 (ITGA9), a cell adhesion receptor, in four of the five fetuses who failed to respond to the OK-432 treatment. Computer modeling of the p.G404S substitution supported the deleterious nature of this mutation. Family analyses in three affected fetuses demonstrated that the heterozygous mutant allele is of parental origin, suggesting an autosomal recessive inheritance of this genetic defect. Conclusions To the best of our knowledge, this is the first insight into the possible link between ITGA9 and CC in human fetuses. The identification of pathogenetic mutations and their possible link to the clinical responses of particular treatments may contribute to better pregnancy counseling and management. Copyright © 2008 John Wiley & Sons, Ltd. [source]

Molecular prenatal diagnosis in a case of an X-linked dominant chondrodysplasia punctata

PRENATAL DIAGNOSIS, Issue 9 2003
N. V. Whittock
Abstract X-linked dominant chondrodysplasia punctata, (CDPX2,MIM302960) also known as Conradi,Hünermann,Happle syndrome, is a rare form of skeletal dysplasia that affects the skeleton, skin, hair, and eyes. The disorder is caused by mutations within the emopamil binding protein (Ebp) that functions as a delta(8), delta(7) sterol isomerase in the cholesterol biosynthesis pathway. To date, over 40 separate mutations have been reported in the Ebp gene, EBP, with no obvious correlation between the molecular defects and the severity of the clinical phenotype. We have studied a 30-year-old woman who presented in adulthood with skin, hair, and mild skeletal defects but no ocular abnormalities and have identified a heterozygous missense mutation within the third transmembrane domain of the protein. In addition, we have performed molecular prenatal testing on her unborn fetus. The results demonstrate inter-familial variability for missense mutations within the emopamil binding protein and add to the molecular data for CDPX2. Copyright © 2003 John Wiley & Sons, Ltd. [source]

Parkin gene variations in late-onset Parkinson's disease: comparison between Norwegian and German cohorts

ACTA NEUROLOGICA SCANDINAVICA, Issue 1 2006
A. M. Schlitter
Objectives ,, Mutations in the Parkin gene can cause autosomal recessive early-onset Parkinson's disease (PD). Recently, Parkin mutations were also suggested to play a role in the commoner late-onset forms of PD. Methods ,, We compared a German cohort of PD patients (95) with a Norwegian cohort of PD patients (96). Both cohorts have predominant late-onset form of PD. Mutation and polymorphism frequencies were compared via single-strand conformation polymorphism and sequence analyses. Results ,, Three heterozygous missense mutations (Arg256Cys, Arg402Cys and Thr240Met) were found in late-onset PD patients in the German patient cohort (1.6%). A missense mutation (Arg402Cys) was also found in one of 149 healthy control subjects (0.3%). Only one heterozygous missense mutation (Arg256Cys) was identified in a Norwegian patient suffering from late-onset PD (0.5%). The frequencies of four known single nucleotide polymorphisms significantly differ between the two distant European populations. Conclusion ,, The results support the hypothesis that heterozygous mutations in the Parkin gene may act as susceptibility alleles for late-onset forms of PD in rare cases. [source]

A variant TGFBI corneal dystrophy from G623D mutation with an unusual amyloidogenic phenotype

ACTA OPHTHALMOLOGICA, Issue 2009
HT AGOSTINI
Purpose To present a unique corneal dystrophy never before described in a German family carrying the Gly623Asp mutation of the TGFBI gene with late clinical onset. Methods Clinical documentation and isolation of genomic DNA from peripheral blood leucocytes were obtained from each family member examined. Exons 3, 4, 5, and 11 to 14 of the TGFBI gene were sequenced. 5 corneal buttons of 3 affected siblings were excised at the time of penetrating keratoplasty. Light and electron microscopic examination were performed including immunohistochemistry with antibodies against Keratoepithelin (KE) 2 and 15. Results Specimens showed changes in Bowman's layer and the adjacent stroma. Congo red-positive amyloid deposits were found within the epithelium in one cornea, in Bowman's layer and in the anterior stroma of all specimens, also showing KE2- but not KE15-immunostaining. EM revealed deposits located in the anterior stroma and Bowman's layer and the basal area of some epithelial cells. These areas were strongly Alcian blue-positive but negative in the Masson-Trichrom-stain. Only affected patients had a heterozygous missense mutation in exon 14 of the TGFBI gene (G->A transition at nucleotide 1915) with the change Gly623Asp in the keratoepithelin protein. Conclusion In contrast to the patient carrying the Gly623Asp mutation of the TGFBI gene described by Afshari et al., our cases presented with Salzmann nodular degeneration like clinical features with KE2 positive amyloid. The reason for this now "meeting the expectation histological phenotype" is unclear. The histological findings emphasize that this is a unique corneal dystrophy which shares no clinical characteristics with Reis-Bücklers dystrophy and should be treated as a distinct entity. [source]

DNA variants in coding region of EFHC1: SNPs do not associate with juvenile myoclonic epilepsy

EPILEPSIA, Issue 5 2009
Dongsheng Bai
Summary Purpose:, Juvenile myoclonic epilepsy (JME) accounts for 3 to 12% of all epilepsies. In 2004, we identified a mutation-harboring Mendelian gene that encodes a protein with one EF-hand motif (EFHC1) in chromosome 6p12. We observed one doubly heterozygous and three heterozygous missense mutations in EFHC1 segregating as an autosomal dominant gene with 21 affected members of six Hispanic JME families from California and Mexico. In 2006, similar and three novel missense mutations were reported in sporadic and familial Caucasian JME from Italy and Austria. In this study, we asked if coding single nucleotide polymorphisms (SNPs) of EFHC1 also contribute as susceptibility alleles to JME with complex genetics. Methods:, We screened using denaturing high-performance liquid chromatography (DHPLC) and then directly sequenced the 11 exons of EFHC1 in 130 unrelated JME probands, their 352 family members, and seven exons of EFHC1 in 400,614 ethnically matched controls. We carried out case-control association studies between 124 unrelated Hispanic JME probands and 552,614 ethnically matched controls using four SNPs, rs3804506, rs3804505, rs1266787, and rs17851770. We also performed family-based association on SNPs rs3804506 and rs3804505 in 84 complete JME families using the Family-Based Association Test (FBAT) program. Results:, We found no statistically significant differences between JME probands and controls in case-control association and no genetic transmission disequilibria in family-based association for the tested SNPs. In addition, we identified four new DNA variants in the coding region of EFHC1. Conclusion:, The four coding SNPs, rs3804506, rs3804505, rs1266787, and rs17851770, of EFHC1 may not be susceptibility alleles for JME. [source]

Actin mutations are one cause of congenital fibre type disproportion

ANNALS OF NEUROLOGY, Issue 5 2004
Nigel G. Laing PhD
We report three heterozygous missense mutations of the skeletal muscle alpha actin gene (ACTA1) in three unrelated cases of congenital fiber type disproportion (CFTD) from Japan and Australia. This represents the first genetic cause of CFTD to be identified and confirms that CFTD is genetically heterogeneous. The three mutations we have identified Leucine221Proline, Aspartate292Valine, and Proline332Serine are novel. They have not been found previously in any cases of nemaline, actin, intranuclear rod, or rod-core myopathy caused by mutations in ACTA1. It remains unclear why these mutations cause type 1 fiber hypotrophy but no nemaline bodies. The three mutations all lie on one face of the actin monomer on the surface swept by tropomyosin during muscle activity, which may suggest a common pathological mechanism. All three CFTD cases with ACTA1 mutations had severe congenital weakness and respiratory failure without ophthalmoplegia. There were no clinical features specific to CFTD cases with ACTA1 mutations, but the presence of normal eye movements in a severe CFTD patient may be an important clue for the presence of a mutation in ACTA1. Ann Neurol 2004 [source]

,-enolase deficiency, a new metabolic myopathy of distal glycolysis

ANNALS OF NEUROLOGY, Issue 2 2001
Giacomo P. Comi MD
A severe muscle enolase deficiency, with 5% of residual activity, was detected in a 47-year-old man affected with exercise intolerance and myalgias. No rise of serum lactate was observed with the ischemic forearm exercise. Ultrastructural analysis showed focal sarcoplasmic accumulation of glycogen , particles. The enzyme enolase catalyzes the interconversion of 2-phosphoglycerate and phosphoenolpyruvate. In adult human muscle, over 90% of enolase activity is accounted for by the ,-enolase subunit, the protein product of the ENO3 gene. The ,-enolase protein was dramatically reduced in the muscle of our patient, by both immunohistochemistry and immunoblotting, while ,-enolase was normally represented. The ENO3 gene of our patient carries two heterozygous missense mutations affecting highly conserved amino acid residues: a G467A transition changing a glycine residue at position 156 to aspartate, in close proximity to the catalytic site, and a G1121A transition changing a glycine to glutamate at position 374. These mutations were probably inherited as autosomal recessive traits since the mother was heterozygous for the G467A and a sister was heterozygous for the G1121A transition. Our data suggest that ENO3 mutations result in decreased stability of mutant ,-enolase. Muscle ,-enolase deficiency should be considered in the differential diagnosis of metabolic myopathies due to inherited defects of distal glycolysis. [source]

Molecular basis of EEC (ectrodactyly, ectodermal dysplasia, clefting) syndrome: five new mutations in the DNA-binding domain of the TP63 gene and genotype,phenotype correlation

BRITISH JOURNAL OF DERMATOLOGY, Issue 1 2010
S.E. Clements
Summary EEC (ectrodactyly, ectodermal dysplasia, clefting; OMIM 604292) syndrome is an autosomal dominant developmental disorder. Characteristic clinical features comprise abnormalities in several ectodermal structures including skin, hair, teeth, nails and sweat glands as well as orofacial clefting and limb defects. Pathogenic mutations in the TP63 transcription factor have been identified as the molecular basis of EEC syndrome and to date 34 mutations have been reported. The majority of mutations involve heterozygous missense mutations in the DNA-binding domain of TP63, a region critical for direct interactions with DNA target sequences. In this report, we present an overview of EEC syndrome, discuss the role of TP63 in embryonic development and skin homeostasis, and report five new TP63 gene mutations. We highlight the significant intra- and interfamilial phenotypic variability in affected individuals and outline the emerging paradigm for genotype,phenotype correlation in this inherited ectodermal dysplasia syndrome. [source]