Publications by authors named "Lise Larrieu"

18 Publications

  • Page 1 of 1

Biallelic RFC1-expansion in a French multicentric sporadic ataxia cohort.

J Neurol 2021 Mar 5. Epub 2021 Mar 5.

Department of Neurology, Strasbourg University Hospital, 1 avenue Molière, 67098, Strasbourg, France.

Objective: Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a recessively inherited multisystem ataxia compromising cerebellar, vestibular, and sensory nerves, which has been associated to a pathogenic AAGGG(n) biallelic expansion repeat in the RFC1 gene. Our objective was to assess its prevalence in a French cohort of patients with idiopathic sporadic late-onset ataxia (ILOA), idiopathic early-onset ataxia (IEOA), or Multiple System Atrophy of Cerebellar type (MSA-C).

Methods: 163 patients were recruited in 3 French tertiary centers: 100 ILOA, 21 IEOA, and 42 patients with possible or probable MSA-C.

Results: A pathogenic biallelic RFC1 AAGGG(n) repeat expansion was found in 15 patients: 15/100 in the ILOA group, but none in the IEOA and MSA-C subgroups. 14/15 patients had a CANVAS phenotype. Only 1/15 had isolated cerebellar ataxia, but also shorter biallelic expansions. Two RFC1 AAGGG(n) alleles were found in 78% of patients with a CANVAS phenotype. In one post-mortem case, the pathophysiological involvement of cerebellum and medullar posterior columns was found.

Conclusion: Our study confirms the genetic heterogeneity of the CANVAS and that RFC1 repeat expansions should be searched for preferentially in case of unexplained ILOA associated with a sensory neuronopathy, but not particularly in patients classified as MSA-C.
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http://dx.doi.org/10.1007/s00415-021-10499-5DOI Listing
March 2021

Expanding the clinical spectrum of STIP1 homology and U-box containing protein 1-associated ataxia.

J Neurol 2021 Jan 8. Epub 2021 Jan 8.

Service de Génétique Médicale, Hôpitaux de Brabois, CHRU de Nancy, Rue du Morvan, 54500, Vandoeuvre-lès-Nancy, France.

Background: STUB1 has been first associated with autosomal recessive (SCAR16, MIM# 615768) and later with dominant forms of ataxia (SCA48, MIM# 618093). Pathogenic variations in STUB1 are now considered a frequent cause of cerebellar ataxia.

Objective: We aimed to improve the clinical, radiological, and molecular delineation of SCAR16 and SCA48.

Methods: Retrospective collection of patients with SCAR16 or SCA48 diagnosed in three French genetic centers (Montpellier, Strasbourg and Nancy).

Results: Here, we report four SCAR16 and nine SCA48 patients from two SCAR16 and five SCA48 unrelated French families. All presented with slowly progressive cerebellar ataxia. Additional findings included cognitive decline, dystonia, parkinsonism and swallowing difficulties. The age at onset was highly variable, ranging from 14 to 76 years. Brain MRI showed marked cerebellar atrophy in all patients. Phenotypic findings associated with STUB1 pathogenic variations cover a broad spectrum, ranging from isolated slowly progressive ataxia to severe encephalopathy, and include extrapyramidal features. We described five new pathogenic variations, two previously reported pathogenic variations, and two rare variants of unknown significance in association with STUB1-related disorders. We also report the first pathogenic variation associated with both dominant and recessive forms of inheritance (SCAR16 and SCA48).

Conclusion: Even though differences are observed between the recessive and dominant forms, it appears that a continuum exists between these two entities. While adding new symptoms associated with STUB1 pathogenic variations, we insist on the difficulty of genetic counselling in STUB1-related pathologies. Finally, we underscore the usefulness of DAT-scan as an additional clue for diagnosis.
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http://dx.doi.org/10.1007/s00415-020-10348-xDOI Listing
January 2021

ATP8A2-related disorders as recessive cerebellar ataxia.

J Neurol 2020 Jan 14;267(1):203-213. Epub 2019 Oct 14.

Laboratoire de Génétique de Maladies Rares EA7402, Institut Universitaire de Recherche Clinique, Université de Montpellier, CHU Montpellier, 640 av. Doyen G. Giraud CEDEX 5, 34295, Montpellier, France.

ATP8A2-related disorders are autosomal recessive conditions that associate encephalopathy with or without hypotonia, psychomotor delay, abnormal movements, chorea, tremor, optic atrophy and cerebellar atrophy (CARMQ4). Through a multi-centric collaboration, we identified six point mutations (one splice site and five missense mutations) involving ATP8A2 in six individuals from five families. Two patients from one family with the homozygous p.Gly585Val mutation had a milder presentation without encephalopathy. Expression and functional studies of the missense mutations demonstrated that protein levels of four of the five missense variants were very low and lacked phosphatidylserine-activated ATPase activity. One variant p.Ile215Leu, however, expressed at normal levels and displayed phospholipid-activated ATPase activity similar to the non-mutated protein. We therefore expand for the first time the phenotype related to ATP8A2 mutations to less severe forms characterized by cerebellar ataxia without encephalopathy and suggest that ATP8A2 should be analyzed for all cases of syndromic or non-syndromic recessive or sporadic ataxia.
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http://dx.doi.org/10.1007/s00415-019-09579-4DOI Listing
January 2020

mutations: A novel phenotype associating severe optic atrophy and spastic paraplegia.

Neurol Genet 2018 Apr 20;4(2):e225. Epub 2018 Mar 20.

Department of Neurology (C.M., B.C.), Gui de Chauliac Montpellier University Hospital; EA7402 Institut Universitaire de Recherche Clinique (C.M., L.L., M.K., C.G.), and Laboratoire de Génétique Moléculaire, University Hospital; Maladies Sensorielles Génétiques (C.H., M.Q., C.D., E.S.), CHRU; INSERM U1051 (C.H., M.Q., C.D., E.S.), Institute for Neurosciences of Montpellier; Université Montpellier (C.H., M.Q., C.D., E.S.), France; INSERM UMR 1141 (D.C., P.R.), PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, France.

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http://dx.doi.org/10.1212/NXG.0000000000000225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5860906PMC
April 2018

Mini-Exome Coupled to Read-Depth Based Copy Number Variation Analysis in Patients with Inherited Ataxias.

Hum Mutat 2016 12 2;37(12):1340-1353. Epub 2016 Sep 2.

EA7402 Institut Universitaire de Recherche Clinique, and Laboratoire de Génétique Moléculaire, University Hospital, Montpellier, France.

Next-generation sequencing (NGS) has an established diagnostic value for inherited ataxia. However, the need of a rigorous process of analysis and validation remains challenging. Moreover, copy number variations (CNV) or dynamic expansions of repeated sequence are classically considered not adequately detected by exome sequencing technique. We applied a strategy of mini-exome coupled to read-depth based CNV analysis to a series of 33 patients with probable inherited ataxia and onset <50 years. The mini-exome consisted of the capture of 4,813 genes having associated clinical phenotypes. Pathogenic variants were found in 42% and variants of uncertain significance in 24% of the patients. These results are comparable to those from whole exome sequencing and better than previous targeted NGS studies. CNV and dynamic expansions of repeated CAG sequence were identified in three patients. We identified both atypical presentation of known ataxia genes (ATM, NPC1) and mutations in genes very rarely associated with ataxia (ERCC4, HSD17B4). We show that mini-exome bioinformatics data analysis allows the identification of CNV and dynamic expansions of repeated sequence. Our study confirms the diagnostic value of the proposed genetic analysis strategy. We also provide an algorithm for the multidisciplinary process of analysis, interpretation, and validation of NGS data.
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http://dx.doi.org/10.1002/humu.23063DOI Listing
December 2016

A false positive newborn screening result due to a complex allele carrying two frequent CF-causing variants.

J Cyst Fibros 2016 05 23;15(3):309-12. Epub 2016 Apr 23.

Laboratoire de Génétique Moléculaire, CHRU Montpellier, 34093 Montpellier Cedex 5, France; Laboratoire de Génétique de Maladies Rares, Institut Universitaire de Recherche Clinique, EA 7402, Université de Montpellier, 34000 Montpellier Cedex 5, France.

The detection of two frequent CFTR disease-causing variations in the context of a newborn screening program (NBS) usually leads to the diagnosis of cystic fibrosis (CF) and a relevant genetic counseling in the family. In the present study, CF-causing variants p.Phe508del (F508del) and c.3140-26A>G (3272-26A>G) were identified on a neonate with positive ImmunoReactive Trypsinogen test by the Elucigene™ CF30 kit. The CF diagnosis initially suggested, despite three inconclusive Sweat Chloride Tests (SCT), was finally ruled out after the familial segregation study combined with a negative SCT. Haplotype studies, based on the comparison of 80 p.Phe508del haplotypes, suggested a probable de novo occurrence of c.3140-26A>G on the p.Phe508del ancestral allele in this family. This false positive case emphasizes the importance of SCT in the NBS strategy. Moreover, it raises the need for familial segregation studies in CF and in overall molecular diagnosis strategy of autosomal recessive diseases.
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http://dx.doi.org/10.1016/j.jcf.2016.04.003DOI Listing
May 2016

Genes for spinocerebellar ataxia with blindness and deafness (SCABD/SCAR3, MIM# 271250 and SCABD2).

Eur J Hum Genet 2016 08 16;24(8):1154-9. Epub 2015 Dec 16.

Equipe d'Accueil 7402, Institut Universitaire de Recherche Clinique, Université de Montpellier, Montpellier, France.

Ataxia is a symptom that is often associated with syndromic inherited diseases. We previously reported the linkage of a novel syndrome, ataxia with blindness and deafness (SCAR3/SCABD, OMIM# 271250), to chromosome 6p21-p23 by linkage mapping of an Arab Israeli consanguineous family. We have now identified by whole-exome sequencing a homozygous missense mutation in the Arab Israeli family in the SLC52A2 gene located in 8qter, therefore excluding linkage of this family to 6p. We confirmed the involvement of SLC52A2 by the identification of a second mutation in an independent family with an identical syndromic presentation, which we suggest to name SCABD2. SCABD2 is therefore allelic to Brown-Vialleto-Van Laere syndrome type 2 defined by prominent motoneuronopathy and deafness, and also caused by SLC52A2 mutations. In the course of this project, we identified a clinically similar family with a homozygous missense mutation in PEX6, which is located in 6p21. Therefore, despite false linkage in the initial family, SCABD1/SCAR3 is located in 6p21 and is caused by PEX6 mutations. Both SLC52A2 and PEX6 should be included in screening panels for the diagnosis of syndromic inherited ataxias, particularly as patients with mutations in SLC52A2 can be ameliorated by riboflavin supplementation.
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http://dx.doi.org/10.1038/ejhg.2015.259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970675PMC
August 2016

Pitfalls in ataxia with ocular motor apraxia type 1: pseudodominant inheritance and very late onset.

J Neurol 2015 May 7;262(5):1366-8. Epub 2015 Apr 7.

Neurologie C, Hospices Civils de Lyon, Hôpital Neurologique Pierre Wertheimer, Lyon, France,

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http://dx.doi.org/10.1007/s00415-015-7717-4DOI Listing
May 2015

Novel deletions involving the USH2A gene in patients with Usher syndrome and retinitis pigmentosa.

Mol Vis 2014 25;20:1398-410. Epub 2014 Sep 25.

Grupo de Investigación en Enfermedades Neurosensoriales, Instituto de Investigación Sanitaria La Fe (IIS-La Fe), Valencia, Spain ; CIBER de Enfermedades Raras (CIBERER), Madrid, Spain ; Unidad de Genética y Diagnóstico Prenatal, Hospital Universitario y Politécnico La Fe, Valencia, Spain.

Purpose: The aim of the present work was to identify and characterize large rearrangements involving the USH2A gene in patients with Usher syndrome and nonsyndromic retinitis pigmentosa.

Methods: The multiplex ligation-dependent probe amplification (MLPA) technique combined with a customized array-based comparative genomic hybridization (aCGH) analysis was applied to 40 unrelated patients previously screened for point mutations in the USH2A gene in which none or only one pathologic mutation was identified.

Results: We detected six large deletions involving USH2A in six out of the 40 cases studied. Three of the patients were homozygous for the deletion, and the remaining three were compound heterozygous with a previously identified USH2A point mutation. In five of these cases, the patients displayed Usher type 2, and the remaining case displayed nonsyndromic retinitis pigmentosa. The exact breakpoint junctions of the deletions found in USH2A in four of these cases were characterized.

Conclusions: Our study highlights the need to develop improved efficient strategies of mutation screening based upon next generation sequencing (NGS) that reduce cost, time, and complexity and allow simultaneous identification of all types of disease-causing mutations in diagnostic procedures.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4173666PMC
June 2015

Enrichment of LOVD-USHbases with 152 USH2A genotypes defines an extensive mutational spectrum and highlights missense hotspots.

Hum Mutat 2014 Oct 15;35(10):1179-86. Epub 2014 Jul 15.

CHU Montpellier, Laboratoire de Génétique Moléculaire, Montpellier, F-34000, France.

Alterations of USH2A, encoding usherin, are responsible for more than 70% of cases of Usher syndrome type II (USH2), a recessive disorder that combines moderate to severe hearing loss and retinal degeneration. The longest USH2A transcript encodes usherin isoform b, a 5,202-amino-acid transmembrane protein with an exceptionally large extracellular domain consisting notably of a Laminin N-terminal domain and numerous Laminin EGF-like (LE) and Fibronectin type III (FN3) repeats. Mutations of USH2A are scattered throughout the gene and mostly private. Annotating these variants is therefore of major importance to correctly assign pathogenicity. We have extensively genotyped a novel cohort of 152 Usher patients and identified 158 different mutations, of which 93 are newly described. Pooling this new data with the existing pathogenic variants already incorporated in USHbases reveals several previously unappreciated features of the mutational spectrum. We show that parts of the protein are more likely to tolerate single amino acid variations, whereas others constitute pathogenic missense hotspots. We have found, in repeated LE and FN3 domains, a nonequal distribution of the missense mutations that highlights some crucial positions in usherin with possible consequences for the assessment of the pathogenicity of the numerous missense variants identified in USH2A.
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http://dx.doi.org/10.1002/humu.22608DOI Listing
October 2014

Experience of targeted Usher exome sequencing as a clinical test.

Mol Genet Genomic Med 2014 Jan 10;2(1):30-43. Epub 2013 Jul 10.

U827, Inserm Montpellier, F-34000, France ; Laboratoire de Génétique Moléculaire, CHU Montpellier Montpellier, F-34000, France.

We show that massively parallel targeted sequencing of 19 genes provides a new and reliable strategy for molecular diagnosis of Usher syndrome (USH) and nonsyndromic deafness, particularly appropriate for these disorders characterized by a high clinical and genetic heterogeneity and a complex structure of several of the genes involved. A series of 71 patients including Usher patients previously screened by Sanger sequencing plus newly referred patients was studied. Ninety-eight percent of the variants previously identified by Sanger sequencing were found by next-generation sequencing (NGS). NGS proved to be efficient as it offers analysis of all relevant genes which is laborious to reach with Sanger sequencing. Among the 13 newly referred Usher patients, both mutations in the same gene were identified in 77% of cases (10 patients) and one candidate pathogenic variant in two additional patients. This work can be considered as pilot for implementing NGS for genetically heterogeneous diseases in clinical service.
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http://dx.doi.org/10.1002/mgg3.25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907913PMC
January 2014

Non-USH2A mutations in USH2 patients.

Hum Mutat 2012 Mar 6;33(3):504-10. Epub 2012 Jan 6.

CHU Montpellier, Laboratoire de Génétique Moléculaire, Montpellier, France.

We have systematically analyzed the two known minor genes involved in Usher syndrome type 2, DFNB31 and GPR98, for mutations in a cohort of 31 patients not linked to USH2A. PDZD7, an Usher syndrome type 2 (USH2) related gene, was analyzed when indicated. We found that mutations in GPR98 contribute significantly to USH2. We report 17 mutations in 10 individuals, doubling the number of GPR98 mutations reported to date. In contrast to mutations in usherin, the mutational spectrum of GPR98 predominantly results in a truncated protein product. This is true even when the mutation affects splicing, and we have incorporated a splicing reporter minigene assay to show this, where appropriate. Only two mutations were found which we believe to be genuine missense changes. Discrepancy in the mutational spectrum between GPR98 and USH2A is discussed. Only two patients were found with mutations in DFNB31, showing that mutations of this gene contribute to only a very small extent to USH2. Close examination of the clinical details, where available, for patients in whom no mutation was found in USH2A, GPR98, or DFNB31, showed that most of them had atypical features. In effect, these three genes account for the vast majority of USH2 patients and their analysis provide a robust pathway for routine molecular diagnosis.
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http://dx.doi.org/10.1002/humu.22004DOI Listing
March 2012

Usher syndrome type 2 caused by activation of an USH2A pseudoexon: implications for diagnosis and therapy.

Hum Mutat 2012 Jan 16;33(1):104-8. Epub 2011 Nov 16.

CHU Montpellier, Laboratoire de Génétique Moléculaire, Montpellier, France.

USH2A sequencing in three affected members of a large family, referred for the recessive USH2 syndrome, identified a single pathogenic alteration in one of them and a different mutation in the two affected nieces. As the patients carried a common USH2A haplotype, they likely shared a mutation not found by standard sequencing techniques. Analysis of RNA from nasal cells in one affected individual identified an additional pseudoexon (PE) resulting from a deep intronic mutation. This was confirmed by minigene assay. This is the first example in Usher syndrome (USH) with a mutation causing activation of a PE. The finding of this alteration in eight other individuals of mixed European origin emphasizes the importance of including RNA analysis in a comprehensive diagnostic service. Finally, this mutation, which would not have been found by whole-exome sequencing, could offer, for the first time in USH, the possibility of therapeutic correction by antisense oligonucleotides (AONs).
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http://dx.doi.org/10.1002/humu.21634DOI Listing
January 2012

Nasal epithelial cells are a reliable source to study splicing variants in Usher syndrome.

Hum Mutat 2010 Jun;31(6):734-41

CHU Montpellier, Laboratoire de Génétique Moléculaire, Montpellier, France.

We have shown that nasal ciliated epithelium, which can be easily biopsied under local anesthetic, provides a good source of RNA transcripts from eight of the nine known genes that cause Usher syndrome, namely, MYO7A, USH1C, CDH23, PCDH15, USH1G for Usher type 1, and USH2A, GPR98, WHRN for Usher type 2. Furthermore, the known or predicted effect on mRNA splicing of eight variants was faithfully reproduced in the biopsied sample as measured by nested RT-PCR. These included changes at the canonical acceptor site, changes within the noncanonical acceptor site and both synonymous and nonsynonymous amino acid changes. This shows that mRNA analysis by this method will help in assessing the pathogenic effect of variants, which is a major problem in the molecular diagnosis of Usher syndrome.
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http://dx.doi.org/10.1002/humu.21255DOI Listing
June 2010

The USH2A c.2299delG mutation: dating its common origin in a Southern European population.

Eur J Hum Genet 2010 Jul 10;18(7):788-93. Epub 2010 Feb 10.

Unidad de Genética, Hospital Universitario La Fe, Valencia, Spain.

Usher syndrome type II is the most common form of Usher syndrome. USH2A is the main responsible gene of the three known to be disease causing. It encodes two isoforms of the protein usherin. This protein is part of an interactome that has an essential role in the development and function of inner ear hair cells and photoreceptors. The gene contains 72 exons spanning over a region of 800 kb. Although numerous mutations have been described, the c.2299delG mutation is the most prevalent in several populations. Its ancestral origin was previously suggested after the identification of a common core haplotype restricted to 250 kb in the 5' region that encodes the short usherin isoform. By extending the haplotype analysis over the 800 kb region of the USH2A gene with a total of 14 intragenic single nucleotide polymorphisms, we have been able to define 10 different c.2299delG haplotypes, showing high variability but preserving the previously described core haplotype. An exhaustive c.2299delG/control haplotype study suggests that the major source of variability in the USH2A gene is recombination. Furthermore, we have evidenced twice the amount of recombination hotspots located in the 500 kb region that covers the 3' end of the gene, explaining the higher variability observed in this region when compared with the 250 kb of the 5' region. Our data confirm the common ancestral origin of the c.2299delG mutation.
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http://dx.doi.org/10.1038/ejhg.2010.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2987359PMC
July 2010

Ex vivo splicing assays of mutations at noncanonical positions of splice sites in USHER genes.

Hum Mutat 2010 Mar;31(3):347-55

Université Montpellier 1, UFR médecine, Montpellier, France.

Molecular diagnosis in Usher syndrome type 1 and 2 patients led to the identification of 21 sequence variations located in noncanonical positions of splice sites in MYO7A, CDH23, USH1C, and USH2A genes. To establish experimentally the splicing pattern of these substitutions, whose impact on splicing is not always predictable by available softwares, ex vivo splicing assays were performed. The branch-point mapping strategy was also used to investigate further a putative branch-point mutation in USH2A intron 43. Aberrant splicing was demonstrated for 16 of the 21 (76.2%) tested sequence variations. The mutations resulted more frequently in activation of a nearby cryptic splice site or use of a de novo splice site than exon skipping (37.5%). This study allowed the reclassification as splicing mutations of one silent (c.7872G>A (p.Glu2624Glu) in CDH23) and four missense mutations (c.2993G>A (p.Arg998Lys) in USH2A, c.592G>A (p.Ala198Thr), c.3503G>C [p.Arg1168Pro], c.5944G>A (p.Gly1982Arg) in MYO7A), whereas it provided clues about a role in structure/function in four other cases: c.802G>A (p.Gly268Arg), c.653T>A (p.Val218Glu) (USH2A), and c.397C>T (p.His133Tyr), c.3502C>T (p.Arg1168Trp) (MYO7A). Our data provide insights into the contribution of splicing mutations in Usher genes and illustrate the need to define accurately their splicing outcome for diagnostic purposes.
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http://dx.doi.org/10.1002/humu.21193DOI Listing
March 2010

UMD-USHbases: a comprehensive set of databases to record and analyse pathogenic mutations and unclassified variants in seven Usher syndrome causing genes.

Hum Mutat 2008 Aug;29(8):E76-87

CHU Montpellier, Laboratoire de Génétique Moléculaire, Montpellier, F-34000, France.

Using the Universal Mutation Database (UMD) software, we have constructed "UMD-USHbases", a set of relational databases of nucleotide variations for seven genes involved in Usher syndrome (MYO7A, CDH23, PCDH15, USH1C, USH1G, USH3A and USH2A). Mutations in the Usher syndrome type I causing genes are also recorded in non-syndromic hearing loss cases and mutations in USH2A in non-syndromic retinitis pigmentosa. Usher syndrome provides a particular challenge for molecular diagnostics because of the clinical and molecular heterogeneity. As many mutations are missense changes, and all the genes also contain apparently non-pathogenic polymorphisms, well-curated databases are crucial for accurate interpretation of pathogenicity. Tools are provided to assess the pathogenicity of mutations, including conservation of amino acids and analysis of splice-sites. Reference amino acid alignments are provided. Apparently non-pathogenic variants in patients with Usher syndrome, at both the nucleotide and amino acid level, are included. The UMD-USHbases currently contain more than 2,830 entries including disease causing mutations, unclassified variants or non-pathogenic polymorphisms identified in over 938 patients. In addition to data collected from 89 publications, 15 novel mutations identified in our laboratory are recorded in MYO7A (6), CDH23 (8), or PCDH15 (1) genes. Information is given on the relative involvement of the seven genes, the number and distribution of variants in each gene. UMD-USHbases give access to a software package that provides specific routines and optimized multicriteria research and sorting tools. These databases should assist clinicians and geneticists seeking information about mutations responsible for Usher syndrome.
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http://dx.doi.org/10.1002/humu.20780DOI Listing
August 2008

Molecular and in silico analyses of the full-length isoform of usherin identify new pathogenic alleles in Usher type II patients.

Hum Mutat 2007 Aug;28(8):781-9

Centre Hospitalier Universitaire (CHU) Montpellier, Laboratoire de Génétique Moléculaire, Montpellier, France.

The usherin gene (USH2A) has been screened for mutations causing Usher syndrome type II (USH2). Two protein isoforms have been identified: a short isoform of 1,546 amino acids and a more recently recognized isoform extending to 5,202 amino acids. We have screened the full length by genomic sequencing. We confirm that many mutations occur in the exons contributing solely to the longer form. USH2 is an autosomal recessive disorder and, in contrast to previous studies, both mutations were identified in 23 patients and a single mutation in 2 out of 33 patients. A total of 34 distinct mutated alleles were identified, including one complex allele with three variants and another with two. A total of 27 of these are novel, confirming that most mutations in usherin are private. Many of the mutations will lead to prematurely truncated protein but as there are a substantial number of missense variants, we have used in silico analysis to assess their pathogenicity. Evidence that they are disease-causing has been produced by protein alignments and three-dimensional (3D) structural predictions when possible. We have identified a previously unrecognized cysteine rich structural domain, containing 12 dicysteine repeats, and show that three missense mutations result in the loss of one of a pair of the defining cysteine-cysteine pairs.
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http://dx.doi.org/10.1002/humu.20513DOI Listing
August 2007