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Hum Mutat [journal]
- Whole-exome Sequencing Identifies a Variant in TMEM132E Causing Autosomal-Recessive Nonsyndromic Hearing Loss DFNB99. [JOURNAL ARTICLE]
- Hum Mutat 2014 Oct 21.
Autosomal recessive non-syndromic hearing loss (ARNSHL) features a high degree of genetic heterogeneity. Many genes responsible for ARNSHL have been identified or mapped. We previously mapped an ARNSHL locus at 17q12, herein designated DFNB99, in a consanguineous Chinese family. In this study, whole-exome sequencing revealed a homozygous missense mutation (c.1259G>A, p.Arg420Gln) in the gene encoding transmembrane protein 132E (TMEM132E) as the causative variant. Immunofluorescence staining of the Organ of Corti showed Tmem132e highly expressed in murine inner hair cells. Furthermore, knockdown of the tmem132e ortholog in zebrafish affected the mechanotransduction of hair cells. Finally, wild-type human TMEM132E mRNA but not the mRNA carrying the c.1259G>A mutation rescued the Tmem132e knockdown phenotype. We conclude that the variant in TMEM132E is the most likely cause of DFNB99. This article is protected by copyright. All rights reserved.
- Next Generation Sequencing Identifies a Novel Rearrangement in the HBB Cluster Permitting to-the-Base Characterization. [JOURNAL ARTICLE]
- Hum Mutat 2014 Oct 21.
Genetic testing for hemoglobinopathies is required for prenatal diagnosis, understanding complex cases where multiple pathogenic variants may be present or investigating cases of unexplained anemia. Characterization of disease causing variants that range from single base changes to large rearrangements, may require several different labor-intensive methodologies. Multiplex ligation probe amplification analysis is the current method used to detect indels, but the technique does not characterize the breakpoints or detect balanced translocations. Here we describe a next generation sequencing (NGS) method that is able to identify and characterize a novel rearrangement of the HBB cluster responsible for εγδβ thalassemia in an English family. The structural variant involved a 59.0 kb inversion encompassing HBG2 exon 3, HBG1, HBD, HBB and OR51V1, juxtaposed by a deletion of 122.6 kb including 82 bp of the inverted sequence, HBG2 exon 1 and 2, HBE, and the β-locus control region. Identification of reads spanning the breakpoints provided to-the-base resolution of the rearrangement, subsequently confirmed by gap-PCR and Sanger sequence analysis. The same rearrangement, termed Inv-Del English V εγδβ thalassemia (HbVar 2935), was identified in two other unrelated English individuals with a similar hematological phenotype. Our NGS approach should be applicable as a diagnostic tool for other disorders. This article is protected by copyright. All rights reserved.
- MAP4 Dependent Regulation of Microtubule Formation Affects Centrosome, Cilia and Golgi Architecture as A Central Mechanism in Growth Regulation. [JOURNAL ARTICLE]
- Hum Mutat 2014 Oct 17.
Numerous genes are involved in human growth regulation. Recently, autosomal recessive inherited variants in centrosomal proteins have been identified in Seckel syndrome, primary microcephaly or microcephalic osteodysplastic primary dwarfism. Common hallmarks of these syndromic forms are severe short stature and microcephaly. In a consanguineous family with two affected children with severe growth retardation and normocephaly we used homozygosity mapping and next generation sequencing to identify a homozygous MAP4 variant. MAP4 is a major protein for microtubule assembly during mitosis. High expression levels in the somite boundaries of zebrafish suggested a role in growth and body segment patterning. The identified variant affects binding sites of kinases necessary for dynamic instability of microtubule formation. We found centrosome amplifications in mitotic fibroblast cells in vivo and in vitro. These numeric centrosomal aberrations were also present during interphase resulting in aberrant ciliogenesis. Furthermore, affected cells showed a dysfunction of the microtubule dependent assembly of the Golgi apparatus, indicated by a significant lack of compactness of Golgi membranes. These observations demonstrated that MAP4 mutations contribute to the clinical spectrum of centrosomal defects and confirmed the complex role of a centrosomal protein in centrosomal, ciliary and Golgi regulation associated with severe short stature. This article is protected by copyright. All rights reserved.
- Clinical Applications and Implications of Common and Founder Mutations in Indian Subpopulations. [JOURNAL ARTICLE]
- Hum Mutat 2014 Oct 17.
South Asian Indians represent a sixth of the world's population and are a racially, geographically, and genetically diverse people. Their unique anthropological structure, prevailing caste system, and ancient religious practices have all impacted the genetic composition of most of the current-day Indian population. With the evolving socio-religious and economic activities of the sub-sects and castes, endogamous and consanguineous marriages became a commonplace. Consequently, the frequency of founder mutations and the burden of heritable genetic disorders rose significantly. Specifically, the incidence of certain autosomal recessive disorders is relatively high in select Indian subpopulations and communities that share common recent ancestry. Although today clinical genetics and molecular diagnostic services are making inroads in India, the high costs associated with the technology and the tests often keep patients from an exact molecular diagnosis, making more customized and tailored tests, such as those interrogating the most common and founder mutations or those that cater to select sects within the population, highly attractive. These tests offer a quick first-hand affordable diagnostic and carrier screening tool. Here we provide a comprehensive catalog of known common mutations and founder mutations in the Indian population and discuss them from a molecular, clinical, and historical perspective. This article is protected by copyright. All rights reserved.
- Identification of Splicing Defects Caused by Mutations in the Dysferlin Gene. [JOURNAL ARTICLE]
- Hum Mutat 2014 Oct 14.
Missense, iso-semantic and intronic mutations are challenging for interpretation in particular for their impact in mRNA. Various tools such as the Human Splicing Finder system (HSF) could be used to predict the impact on splicing, however no diagnosis result could rely on predictions alone, but requires functional testing. Here we report an in vitro approach to study the impact of DYSF mutations on splicing. It was evaluated on a series of 45 DYSF mutations, both intronic and exonic. We confirmed splicing alterations for all intronic mutations localized in 5' or 3' splice sites. Then, we showed that DYSF missense mutations could also result in splicing defects: mutations c.463G>A and c.2641A>C abolished ESEs and led to exon skipping; mutations c.565C>G and c.1555G>A, disrupted ESE, while concomitantly creating new 5' or 3' splice site leading to exonic out of frame deletions. We demonstrated that 20% of DYSF missense mutations have a strong impact on splicing. This minigene strategy is an efficient tool for the detection of splicing defects in dysferlinopathies, which could allow for a better comprehension of splicing defects due to mutations and could improve prediction tools evaluating splicing defects. This article is protected by copyright. All rights reserved.
- De novo Mutations in the Motor Domain of KIF1A Cause Cognitive Impairment, Spastic Paraparesis, Axonal Neuropathy and Cerebellar Atrophy. [JOURNAL ARTICLE]
- Hum Mutat 2014 Sep 29.
KIF1A is a neuron specific motor protein that plays important roles in cargo transport along neurites. Recessive mutations in KIF1A were previously described in families with spastic paraparesis or sensory and autonomic neuropathy type-2. Here, we report 11 heterozygous de novo missense mutations (p.S58L, p.T99M, p.G102D, p.V144F, p.R167C, p.A202P, p.S215R, p.R216P, p.L249Q, p.E253K, p.R316W) in KIF1A in 14 individuals, including two monozygotic twins. Two mutations (p.T99M and p.E253K) were recurrent, each being found in unrelated cases. All these de novo mutations are located in the motor domain of KIF1A. Structural modeling revealed that they alter conserved residues that are critical for the structure and function of the motor domain. Transfection studies suggested that at least five of these mutations affect the transport of the motor domain along axons. Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, and peripheral neuropathy, and epilepsy. Our findings thus indicate that de novo missense mutations in the motor domain of KIF1A cause a phenotype that overlaps with, while being more severe, than that associated with recessive mutations in the same gene. This article is protected by copyright. All rights reserved.
- Genetics and Pathogenesis of Autosomal Dominant Polycystic Kidney Disease: Twenty Years On. [JOURNAL ARTICLE]
- Hum Mutat 2014 Sep 29.
Autosomal dominant polycystic kidney disease (ADPKD), the most common inherited kidney disorder, is characterized by the progressive development and expansion of bilateral fluid-filled cysts derived from the renal tubule epithelial cells. Although typically leading to end-stage renal disease in late middle age, ADPKD represents a continuum, from neonates with hugely enlarged cystic kidneys to cases with adequate kidney function into old age. Since the identification of the first causative gene (i.e., PKD1, encoding polycystin 1) 20 years ago, genetic studies have uncovered a large part of the key factors that underlie the phenotype variability. Here, we provide a comprehensive review of these significant advances as well as those related to disease pathogenesis models, including mutation analysis of PKD1 and PKD2 (encoding polycystin 2), current mutation detection rate, allelic heterogeneity, genotype and phenotype relationships (in terms of three different inheritance patterns: classical autosomal dominant inheritance, complex inheritance, and somatic and germline mosaicism), modifier genes, the role of second somatic mutation hit in renal cystogenesis, and findings from mouse models of polycystic kidney disease. Based upon a combined consideration of the current knowledge, we attempted to propose a unifying framework for explaining the phenotype variability in ADPKD. This article is protected by copyright. All rights reserved.
- A Genetic Variant in the Seed Region of Mir-4513 Shows Pleiotropic Effects on Lipid and Glucose Homeostasis, Blood Pressure and Coronary Artery Disease. [JOURNAL ARTICLE]
- Hum Mutat 2014 Sep 25.
MicroRNAs (miRNA) play a crucial role in the regulation of diverse biological processes by post-transcriptional modulation of gene expression. Genetic polymorphisms in miRNA-related genes can potentially contribute to a wide range of phenotypes. The effect of such variants on cardiometabolic diseases has not yet been defined. We systematically investigated the association of genetic variants in the seed regions of miRNAs with cardiometabolic phenotypes, using the thus far largest genome wide association studies on 17 cardiometabolic traits/diseases. We found that rs2168518:G>A, a seed region variant of miR-4513, associates with fasting glucose, LDL-cholesterol and total cholesterol, systolic and diastolic blood pressure and risk of coronary artery disease. We experimentally showed that miR-4513 expression is significantly reduced in presence of the rs2168518 mutant allele. We sought to identify miR-4513 target genes that may mediate these associations and revealed five genes (PCSK1, BNC2, MTMR3, ANK3 and GOSR2) through which these effects might be taking place. Using luciferase reporter assays we validated GOSR2 as a target of miR-4513 and further demonstrated that the miRNA mediated regulation of this gene is changed by rs2168518. Our findings indicate a pleiotropic effect of miR-4513 on cardiometabolic phenotypes and may improve our understanding of the pathophysiology of cardiometabolic diseases. This article is protected by copyright. All rights reserved.
- Redefining Mutational Spectra via Updated Locus-specific Databases. [Journal Article]
- Hum Mutat 2014 Oct; 35(10):v.
- Contents. [Journal Article]
- Hum Mutat 2014 Oct; 35(10):i-iii.