Insertion of β-satellite repeats identifies a transmembrane protease causing both congenital and childhood onset autosomal recessive deafness

Scott, Hamish S.; Kudoh, Jun; Wattenhofer, Marie; Shibuya, Kazunori; Berry, Asher; Chrast, Roman; Guipponi, Michel; Wang, Jun; Kawasaki, Kazuhiko; Asakawa, Shuichi; Minoshima, Shinsei; Younus, Farah; Mehdi, S. Qasim; Radhakrishna, Uppala; Papasavvas, Marie Pierre; Gehrig, Corinne; Rossier, Colette; Korostishevsky, Michael; Gal, Andreas; Shimizu, Nobuyoshi; Bonné‐Tamir, Batsheva; Antonarakis, Stylianos E.

doi:10.1038/83768

Cited by 214 publications

(174 citation statements)

References 24 publications

Supporting

Mentioning

167

Contrasting

Unclassified

Order By: Relevance

“…1 -4 Among all DFNB loci, the most prevalent one is DFNB1 (GJB2 and GJB6 genes, 5 -6 MIM 121011 and 604418) that accounts for up to 50% of recessive cases. Other loci with a significant number of different families associated are DFNB4 (SLC26A4 gene, 7 MIM 605646), DFNB9 (OTOF gene, 8 MIM 603681), DFNB12 (CDH23 gene, 9 MIM 605516), DFNB7/11 (TMC1 gene, 10 MIM 606706), followed by DFNB8/10 (TMPRSS3 gene, 11 MIM 605511) and DFNB3 (MYO15A gene, 12 MIM 602666).…”

Section: Introductionmentioning

confidence: 99%

Unexpected genetic heterogeneity in a large consanguineous Brazilian pedigree presenting deafness

et al. 2007

View full text Add to dashboard Cite

Nonsyndromic autosomal recessive deafness accounts for 80% of hereditary deafness. To date, 52 loci responsible for autosomal recessive deafness have been mapped and 24 genes identified. Here, we report a large inbred Brazilian pedigree with 26 subjects affected by prelingual deafness. Given the extensive consanguinity found in this pedigree, the most probable pattern of inheritance is autosomal recessive. However, our linkage and mutational analysis revealed, instead of an expected homozygous mutation in a single gene, two different mutant alleles and a possible third undetected mutant allele in the MYO15A gene (DFNB3 locus), as well as evidence for other causes for deafness in the same pedigree. Among the 26 affected subjects, 15 were homozygous for the novel c.10573delA mutation in the MYO15A gene, 5 were compound heterozygous for the mutation c.10573delA and the novel deletion c.9957_9960delTGAC and one inherited only a single c.10573delA mutant allele, while the other one could not be identified. Given the extensive consanguinity of the pedigree, there might be at least one more deafness locus segregating to explain the condition in some of the subjects whose deafness is not clearly associated with MYO15A mutations, although overlooked environmental causes could not be ruled out. Our findings illustrate a high level of etiological heterogeneity for deafness in the family and highlight some of the pitfalls of genetic analysis of large genes in extended pedigrees, when homozygosity for a single mutant allele is expected.

show abstract

Section: Introductionmentioning

confidence: 99%

Unexpected genetic heterogeneity in a large consanguineous Brazilian pedigree presenting deafness

et al. 2007

View full text Add to dashboard Cite

show abstract

“…9 Genomic DNA from 238 probands and 58 additional deaf relatives from 20 extended families were fully sequenced for both exons of connexin 26, as described. 10 In addition, all individuals were tested for deafness-associated alleles previously identified in families of Palestinian origin: Otoancorin.1067A4T, SLC26A4.716T4A, SLC26A4.1001G4T, TMPRSS3.988delA, TRIOBP.1039C4T, TRIOBP.1741C4T, 8,11 Otoferlin.2416 T4A, 3 TECTA.IVS9(+1)G4A, 4 Otoancorin.IVS12(+2)G4T, 5 the b-satellite insertion of TMPRSS3, 6 and Whirlin.2332C4T. 7 …”

Section: Excluding Known Palestinian Deafness Allelesmentioning

confidence: 99%

“…In particular, Palestinian families with nonsyndromic hearing loss (NSHL) have been a valuable genetic resource for the identification of genes essential for normal hearing. [3][4][5][6][7][8] Homozygosity mapping with SNPs has proven an effective approach to the identification of these genes, because persons with a recessive phenotype and born of a consanguineous union are likely to be homozygous both for the causative mutation and for polymorphisms in the genomic region surrounding the mutation. In this study, we used high-density SNP arrays to genotype the DNA of 155 relatives from 20 consanguineous families with autosomal recessive NSHL.…”

Section: Introductionmentioning

confidence: 99%

Five novel loci for inherited hearing loss mapped by SNP-based homozygosity profiles in Palestinian families

et al. 2009

View full text Add to dashboard Cite

In communities with high rates of consanguinity and consequently high prevalence of recessive phenotypes, homozygosity mapping with SNP arrays is an effective approach for gene discovery. In 20 Palestinian kindreds with prelingual nonsyndromic hearing loss, we generated homozygosity profiles reflecting linkage to the phenotype. Family sizes ranged from small nuclear families with two affected children, one unaffected sibling, and parents to multigenerational kindreds with 12 affected relatives. By including unaffected parents and siblings and screening 250 K SNP arrays, even small nuclear families yielded informative profiles. In 14 families, we identified the allele responsible for hearing loss by screening a single candidate gene in the longest homozygous region. Novel alleles included missense, nonsense, and splice site mutations of CDH23, MYO7A, MYO15A, OTOF, PJVK, Pendrin/SLC26A4, TECTA, TMHS, and TMPRSS3, and a large genomic deletion of Otoancorin (OTOA). All point mutations were rare in the Palestinian population (zero carriers in 288 unrelated controls); the carrier frequency of the OTOA genomic deletion was 1%. In six families, we identified five genomic regions likely to harbor novel genes for human hearing loss on chromosomes 1p13.3 (DFNB82), 9p23-p21.2/p13.3-q21.13 (DFNB83), 12q14.3-q21.2 (DFNB84; two families), 14q23.1-q31.1, and 17p12-q11.2 (DFNB85).

show abstract

“…Likewise, gene targeting studies in mice suggested a function for hepsin in adult liver homeostasis (29,30). Most recently, critical functions of the two TTSPs matriptase/ MT-SP1 and TMPRSS3 in epidermal and inner ear development, respectively, were revealed by gene targeting in mice (31,32) and by the identification of loss of function mutations in TMPRSS3 as the underlying cause of congenital and childhoodonset sensorineural nonsyndromic deafness in humans, respectively (33)(34)(35). Furthermore, several recent studies have demonstrated the aberrant expression of many TTSPs in human cancer, and in some cases, increased TTSP expression correlated with a poor prognosis (15, 17, 36 -44).…”

mentioning

confidence: 99%

Mouse DESC1 Is Located within a Cluster of Seven DESC1-like Genes and Encodes a Type II Transmembrane Serine Protease That Forms Serpin Inhibitory Complexes

Hobson

Netzel‐Arnett

Szabo

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

We report the identification and functional analysis of a type II transmembrane serine protease encoded by the mouse differentially expressed in squamous cell carcinoma (DESC) 1 gene, and the definition of a cluster of seven homologous DESC1-like genes within a 0.5-Mb region of mouse chromosome 5E1. This locus is syntenic to a region of human chromosome 4q13.3 containing the human orthologues of four of the mouse DESC1-like genes. Bioinformatic analysis indicated that all seven DESC1-like genes encode functional proteases. Direct cDNA cloning showed that mouse DESC1 encodes a multidomain serine protease with an N-terminal signal anchor, a SEA (sea urchin sperm protein, enterokinase, and agrin) domain, and a C-terminal serine protease domain. The mouse DESC1 mRNA was present in epidermal, oral, and male reproductive tissues and directed the translation of a membrane-associated 60-kDa N-glycosylated protein with type II topology. Mouse DESC1 was synthesized in insect cells as a zymogen that could be activated by exposure to trypsin. The purified activated DESC1 hydrolyzed synthetic peptide substrates, showing a preference for Arg in the P 1 position. DESC1 proteolytic activity was abolished by generic inhibitors of serine proteases but not by other classes of protease inhibitors. Most interestingly, DESC1 formed stable inhibitory complexes with both plasminogen activator inhibitor-1 and protein C inhibitor that are expressed in the same tissues with DESC1, suggesting that type II transmembrane serine proteases may be novel targets for serpin inhibition. Together, these data show that mouse DESC1 encodes a functional cell surface serine protease that may have important functions in the epidermis, oral, and reproductive epithelium.Pericellular proteolysis is essential to all aspects of vertebrate life, including development, tissue homeostasis, tissue remodeling, tissue repair, and reproduction, and dysregulated pericellular proteolysis is causally related to a large number of diseases in humans. Within the past century, the most extensive studies of pericellular proteolysis in health and disease focused on defining the contribution of a relatively limited number of proteases belonging to the families of plasminogen activators, matrix metalloproteinases, and cathepsins (1-6). However, the recent completion of the mouse and human genome sequences, and the generation of extensive mouse and human EST 1 data bases, facilitated an explosion in the discovery of novel candidate protease genes, indicating that a vastly larger repertoire of pericellular proteases may be engaged in these processes than previously anticipated (7,8). Particularly noteworthy in this context was the unveiling of an unexpectedly large family of type II transmembrane serine proteases (TTSPs) (9 -23). This rapidly expanding family of serine proteases is defined by the presence of an N-terminal signal anchor and a C-terminal serine protease domain, separated by a stem region containing an array of protein domains that varies widely between individual...

show abstract

Insertion of β-satellite repeats identifies a transmembrane protease causing both congenital and childhood onset autosomal recessive deafness

Cited by 214 publications

References 24 publications

Unexpected genetic heterogeneity in a large consanguineous Brazilian pedigree presenting deafness

Unexpected genetic heterogeneity in a large consanguineous Brazilian pedigree presenting deafness

Five novel loci for inherited hearing loss mapped by SNP-based homozygosity profiles in Palestinian families

Mouse DESC1 Is Located within a Cluster of Seven DESC1-like Genes and Encodes a Type II Transmembrane Serine Protease That Forms Serpin Inhibitory Complexes

Contact Info

Product

Resources

About