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Disease Mutations (disease + mutation)
Selected AbstractsThe underrecognized progressive nature of N370S Gaucher disease and assessment of cancer risk in 403 patients,AMERICAN JOURNAL OF HEMATOLOGY, Issue 4 2009Tamar H. Taddei Mutations in GBA1 gene that encodes lysosomal glucocerebrosidase result in Type 1 Gaucher Disease (GD), the commonest lysosomal storage disorder; the most prevalent disease mutation is N370S. We investigated the heterogeneity and natural course of N370S GD in 403 patients. Demographic, clinical, and genetic characteristics of GD at presentation were examined in a cross-sectional study. In addition, the relative risk (RR) of cancer in patients compared with age-, sex-, and ethnic-group adjusted national rates of cancer was determined. Of the 403 patients, 54% of patients were homozygous (N370S/N370S) and 46% were compound heterozygous for the N370S mutation (N370S/other). The majority of N370S/N370S patients displayed a phenotype characterized by late onset, predominantly skeletal disease, whereas the majority of N370S/other patients displayed early onset, predominantly visceral/hematologic disease, P < 0.0001. There was a striking increase in lifetime risk of multiple myeloma in the entire cohort (RR 25, 95% CI 9.17,54.40), mostly confined to N370S homozygous patients. The risk of other hematologic malignancies (RR 3.45, 95% CI 1.49,6.79), and overall cancer risk (RR 1.80, 95% CI 1.32,2.40) was increased. Homozygous N370S GD leads to adult-onset progressive skeletal disease with relative sparing of the viscera, a strikingly high risk of multiple myeloma, and an increased risk of other cancers. High incidence of gammopathy suggests an important role of the adaptive immune system in the development of GD. Adult patients with GD should be monitored for skeletal disease and cancers including multiple myeloma. Am. J. Hematol., 2009. © 2009 Wiley-Liss, Inc. [source] Longitudinal study evaluating neuropsychological changes in so-called asymptomatic carriers of the Huntington's disease mutation after 1 yearACTA NEUROLOGICA SCANDINAVICA, Issue 3 2002J. Lemiere Objectives, To determine (1) whether the battery of neuropsychological tests was sufficiently sensitive to find differences between symptomatic patients with Huntington's disease (HD) and clinically asymptomatic individuals carrying the HD gene (AGC) and individuals without the HD gene (NGC) and (2) whether increasing cognitive impairment is found in AGC as compared with NGC. Methods, A case,control, single-blind study comparing subjects with clinically manifest HD (n=21), AGC (n=12) or NGC (n=11) and a 1-year follow-up of AGC and NGC. Genotype for the HD gene was determined by molecular testing. A large battery of neuropsychological tests measuring several cognitive domains was performed. Results, On most neuropsychological tasks, HD patients perform significantly worse than AGC and NGC. At baseline and follow-up examination, compared with NGC, AGC had lower scores on the symbol digit modalities test. Scores on a block span task declined more rapidly among AGC than among NGC. Conclusion, Cognitive impairments in HD patients are found when compared with clinically asymptomatic individuals carrying the HD mutation. Furthermore, our results suggest that subtle cognitive deficits are present in asymptomatic persons who have inherited the HD gene. [source] Heritability of plasma amyloid , in typical late-onset Alzheimer's disease pedigreesGENETIC EPIDEMIOLOGY, Issue 1 2001Nilufer Ertekin-Taner Abstract Plasma amyloid ,42 peptide (A,42) levels are significantly elevated in all genetic forms of early-onset Alzheimer's disease caused by familial Alzheimer's disease mutations or Down's syndrome. Moreover, recent studies have determined that both plasma A,42 and A,40 levels are significantly elevated in late-onset Alzheimer's disease (LOAD) patients, their cognitively normal first-degree relatives, and members of typical LOAD families when compared to appropriate controls. To determine the magnitude of the genetic component affecting plasma A, levels, we estimated the heritability of plasma A,42 and A,40 in 15 extended, multigenerational LOAD pedigrees, using a variance components method. Heritability estimates as high as 73 and 54% were found for plasma A,42 and A,40 levels, respectively. Inclusion of the ApoE ,4 dosage as a covariate was not found to have a significant effect on the heritability of these traits. These results suggest that genetic determinants other than ApoE account for a very substantial percentage of the phenotypic variance in plasma A, levels. The high heritability and the significant elevation of these traits in LOAD pedigrees suggest that at least some of the genetic determinants of plasma A, levels may lead to elevated A, and LOAD in these families. Thus, we suggest that plasma A, levels are quantitative traits that may be excellent surrogate markers for use in linkage analysis to identify loci that are important in typical LOAD. Genet. Epidemiol. 21:19,30, 2001. © 2001 Wiley-Liss, Inc. [source] Characterization of mutations in ATP8B1 associated with hereditary cholestasisHEPATOLOGY, Issue 1 2004Leo W. J. Klomp Progressive familial intrahepatic cholestasis (PFIC) and benign recurrent intrahepatic cholestasis (BRIC) are clinically distinct hereditary disorders. PFIC patients suffer from chronic cholestasis and develop liver fibrosis. BRIC patients experience intermittent attacks of cholestasis that resolve spontaneously. Mutations in ATP8B1 (previously FIC1) may result in PFIC or BRIC. We report the genomic organization of ATP8B1 and mutation analyses of 180 families with PFIC or BRIC that identified 54 distinct disease mutations, including 10 mutations predicted to disrupt splicing, 6 nonsense mutations, 11 small insertion or deletion mutations predicted to induce frameshifts, 1 large genomic deletion, 2 small inframe deletions, and 24 missense mutations. Most mutations are rare, occurring in 1,3 families, or are limited to specific populations. Many patients are compound heterozygous for 2 mutations. Mutation type or location correlates overall with clinical severity: missense mutations are more common in BRIC (58% vs. 38% in PFIC), while nonsense, frameshifting, and large deletion mutations are more common in PFIC (41% vs. 16% in BRIC). Some mutations, however, lead to a wide range of phenotypes, from PFIC to BRIC or even no clinical disease. ATP8B1 mutations were detected in 30% and 41%, respectively, of the PFIC and BRIC patients screened. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html) and at www.atp8b1-primers.nl (HEPATOLOGY 2004;40:27,38.) [source] The neuronal ceroid lipofuscinosis protein CLN5: new insights into cellular maturation, transport, and consequences of mutations,HUMAN MUTATION, Issue 3 2010Mia-Lisa Schmiedt Abstract Neuronal ceroid lipofuscinoses (NCLs) represent a group of children's inherited neurodegenerative disorders caused by mutations in at least eight different genes. Mutations in the CLN5 gene result in the Finnish variant late infantile NCL characterized by gradual loss of vision, epileptic seizures, and mental deterioration. The CLN5 gene encodes a lysosomal glycoprotein of unidentified function. In this study, we have used both transient and stable expression systems for the characterization of CLN5, focusing on the localization, processing, and intracellular trafficking. We show that CLN5 is proteolytically cleaved, and that the mature polypeptide is transported to the lysosomes. Our data provide the first evidence that soluble CLN5 protein can also undergo mannose-6-phosphate receptor-independent trafficking to the lysosomes. We studied the localization and maturation of the CLN5 carrying the previously uncharacterized vLINCL disease causing mutations in HeLa cells. All analyzed disease mutations disturb the lysosomal trafficking of the mutated CLN5 proteins. The level of lysosomal targeting does not correlate, however, to disease onset, indicating that CLN5 may also function outside lysosomes. This study furthers our understanding of the basic properties of the CLN5 protein, necessary for the characterization of the consequences of disease mutations and for the planning of future therapies for vLINCL. Hum Mutat 31:356,365, 2010. © 2010 Wiley-Liss, Inc. [source] Histological characterization of Darier's disease in Tunisian familiesJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 10 2009S Kassar Abstract Background, Darier's disease (OMIM 124200) is an autosomal-dominant skin disorder characterized by warty papules and plaques in seborreheic areas, palmo-plantar pits and distinctive nail abnormalities. The disease has complete penetrance in adults and variable expressivity. It is caused by mutations in the ATP2A2 gene, which encodes the sarco/endoplasmic reticulum Ca2+ ATPase type 2 isoform (SERCA2). Objective, We report histological investigations of six unrelated Tunisian families including 15 affected individuals with Darier's disease mutations. Results, The typical histological features of Darier's disease have been observed in the 15 patients. Variable histological features have been observed among Tunisian patients ranging from mild to moderate lesions of Darier's disease. A significant correlation has been observed between the clinical presentation of the Darier's disease (mild or moderate) and the intensity of the histological features. Isolated acral form of Darier's disease was seen in one case. Two distinct original associations have been observed: Darier's disease/pemphigus vulgaris in one patient and Darier's disease/ichtyosis in the other patient. Conclusion, Our findings confirmed the clinical heterogeneity of Darier's disease on the basis of histological study. The intensity of the histological features could be closely correlated to the severity of Darier's disease clinical presentation. [source] Type 2 A (group II) von Willebrand disease mutations increase the susceptibility of VWF to ADAMTS-13JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 11 2004H.-M. Tsai [source] | |||||||||||||