Mutations of LRTOMT, a fusion gene with alternative reading frames, cause nonsyndromic deafness in humans

Ahmed, Zubair M.; Masmoudi, Saber; Kalay, Ersan; Belyantseva, Inna A.; Mosrati, Mohamed Ali; Collin, Rob W.J.; Riazuddin, Saima; Hmani-Aifa, Mounira; Venselaar, Hanka; Kawar, Mayya N; Tlili, Abdelaziz; Zwaag, Bert van der; Khan, Shahid Y.; Ayadi, Leila; Morell, Robert J.; Griffith, Andrew J.; Charfedine, Ilhem; Çaylan, Refik; Oostrik, Jaap; Karagüzel, Ahmet; Ghorbel, Abdelmonem; Riazuddin, Sheikh; Friedman, Thomas B.; Ayadi, Hammadi; Kremer, Hannie

doi:10.1038/ng.245

Cited by 62 publications

(71 citation statements)

References 30 publications

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“…We show in this study that the relatively common deafness genes following GJB2 are MYO15A, TMC1, TMIE, and OTOF in Turkey. Five of the 11 genes we found mutated in this study have been reported in other families from Turkey, supporting our findings for their relatively high frequency in the Turkish population (Tekin et al, 2003(Tekin et al, , 2005Kalay et al, 2005Kalay et al, , 2007Wattenhofer et al, 2005;Ahmed et al, 2008). In addition, mutations in MYO15A, TMC1, and OTOF were reported with 5%, 3.4%, and 2.3% frequencies, respectively, in the deaf populations from Pakistan (Kitajiri et al, 2007;Nal et al, 2007;Choi et al, 2009), and mutations in MYO15A and TMC1 were found in 7.8% and 3.9%, respectively, of families without GJB2 mutations from Tunisia (Tlili et al, 2008;Belguith et al, 2009).…”

Section: Discussionsupporting

confidence: 92%

Screening of 38 Genes Identifies Mutations in 62% of Families with Nonsyndromic Deafness in Turkey

Duman

Sırmacı

Cengiz

et al. 2011

Genetic Testing and Molecular Biomarkers

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More than 60% of prelingual deafness is genetic in origin, and of these up to 95% are monogenic autosomal recessive traits. Causal mutations have been identified in 1 of 38 different genes in a subset of patients with nonsyndromic autosomal recessive deafness. In this study, we screened 49 unrelated Turkish families with at least three affected children born to consanguineous parents. Probands from all families were negative for mutations in the GJB2 gene, two large deletions in the GJB6 gene, and the 1555A>G substitution in the mitochondrial DNA MTRNR1 gene. Each family was subsequently screened via autozygosity mapping with genomewide single-nucleotide polymorphism arrays. If the phenotype cosegregated with a haplotype flanking one of the 38 genes, mutation analysis of the gene was performed. We identified 22 different autozygous mutations in 11 genes, other than GJB2, in 26 of 49 families, which overall explains deafness in 62% of families. Relative frequencies of genes following GJB2 were MYO15A (9.9%), TMIE (6.6%), TMC1 (6.6%), OTOF (5.0%), CDH23 (3.3%), MYO7A (3.3%), SLC26A4 (1.7%), PCDH15 (1.7%), LRTOMT (1.7%), SERPINB6 (1.7%), and TMPRSS3 (1.7%). Nineteen of 22 mutations are reported for the first time in this study. Unknown rare genes for deafness appear to be present in the remaining 23 families.

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Section: Discussionsupporting

confidence: 92%

Screening of 38 Genes Identifies Mutations in 62% of Families with Nonsyndromic Deafness in Turkey

Duman

Sırmacı

Cengiz

et al. 2011

Genetic Testing and Molecular Biomarkers

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“…Examples include POMZP3, formed by fusion of the POM121 membrane glycoprotein and ZP3 (zona pellucida glycoprotein 3) 3-5 million years ago, 23 USP6, a hominoidspecific fusion formed by the fusion of USP32 and TBC1D3 approximately 21-33 million years ago, 24 and LRTOMT, a candidate catechol-O-methyltransferase that is mutated in non-syndromic deafness. 25 The finding of the TFG-GPR128 polymorphism may thus be viewed as an intermediate step in evolution that could theoretically culminate in fixation or elimination.…”

Section: Discussionmentioning

confidence: 99%

TFG, a target of chromosome translocations in lymphoma and soft tissue tumors, fuses to GPR128 in healthy individuals

Chase¹,

Ernst²,

Fiebig³

et al. 2009

Haematologica

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The online version of this article has a supplementary appendix. BackgroundThe formation of fusion genes plays roles in both oncogenesis and evolution by facilitating the acquisition of novel functions. Here we describe the first example of a human polymorphic in-frame fusion of two unrelated genes associated with a copy number variant. Design and MethodsArray comparative genomic hybridization was used to identify cryptic oncogenic fusion genes. Fusion gene structure and origin was examined using molecular biological and computational methods. Phenotype associations were examined using PopGen cohorts. ResultsTargeted array comparative genomic hybridization to identify cryptic oncogenic fusion genes in patients with atypical myeloproliferative neoplasms identified a 111 kb amplification with breakpoints within the TRK-fused gene (TFG, a target of translocations in lymphoma and thyroid tumors) and G-protein-coupled receptor 128 (GPR128) resulting in an expressed in-frame TFG-GPR128 fusion transcript. The fusion gene was also identified in healthy individuals at a frequency of 0.02 (3/120). Normally both genes are in identical orientations with TFG immediately downstream of GPR128. In individuals with a copy number variant amplification, one or two copies of the TFG-GPR128 fusion are found between the two parental genes. The breakpoints share a region of microhomology, and haplotype and microsatellite analysis indicate a single ancestral origin. Analysis of PopGen cohorts showed no obvious phenotype association. An in silico search of EST databases found no other copy number variant amplification-associated fusion transcripts, suggesting that this is an uncommon event. ConclusionsThe finding of a polymorphic gene fusion in healthy individuals adds another layer to the complexity of human genome variation and emphasizes the importance of careful discrimination of oncogenic changes found in tumor samples from non-pathogenic normal variation.Key words: fusion gene, oncogenesis, targeted array, array genomic comparative hybridization.Citation: Chase A, Ernst T, Fiebig A, Collins A, Grand F, Erben P, Reiter A, Schreiber S, and Cross NCP. TFG, a target of chromosome translocations in lymphoma and soft tissue tumors, fuses to GPR128 in healthy individuals. Haematologica. 2010;95:20-26. doi:10.3324/haematol.2009 This is an open-access paper. TFG, a target of chromosome translocations in lymphoma and soft tissue tumors, fuses to GPR128 in healthy individuals

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“…Such ''dualcoding'' regions can involve ORFs on the same strand, but in an alternate ''shifted'' reading frame, which can be mediated by alternative splicing, internal translation initiation, or ribosomal frameshifting. Of the six long human dual-coding gene structures for which likely biological functions have been demonstrated (Sharpless and DePinho 1999;Klemke et al 2001;Yoshida et al 2001;Hameed et al 2003;Poulin et al 2003;Ahmed et al 2008), all show at least some evidence of overlapping evolutionary constraint in our analysis: XBP1, GNAS, and the ANKHD1/EIF4EBP3 fusion transcript contain SCEs in their dual-coding regions; the dual-coding 39 end IGF1 narrowly missed our threshold with a 47% reduced synonymous rate; and the dual-coding regions of CDKN2A and LRTOMT have very low synonymous rates, but were excluded from SCEs because of elevated nonsynonymous rates. Aside from these individually studied examples, CCDS annotates 237 other exons as protein-coding in multiple reading frames of the same strand, 24 (10.1%) of which contain SCEs, compared to six (2.5%) containing random control regions.…”

Section: Sces In Known and Novel Dual-coding Genesmentioning

confidence: 99%

Locating protein-coding sequences under selection for additional, overlapping functions in 29 mammalian genomes

Lin¹,

Kheradpour²,

Washietl³

et al. 2011

Genome Res.

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The degeneracy of the genetic code allows protein-coding DNA and RNA sequences to simultaneously encode additional, overlapping functional elements. A sequence in which both protein-coding and additional overlapping functions have evolved under purifying selection should show increased evolutionary conservation compared to typical protein-coding genes-especially at synonymous sites. In this study, we use genome alignments of 29 placental mammals to systematically locate short regions within human ORFs that show conspicuously low estimated rates of synonymous substitution across these species. The 29-species alignment provides statistical power to locate more than 10,000 such regions with resolution down to nine-codon windows, which are found within more than a quarter of all human protein-coding genes and contaiñ 2% of their synonymous sites. We collect numerous lines of evidence that the observed synonymous constraint in these regions reflects selection on overlapping functional elements including splicing regulatory elements, dual-coding genes, RNA secondary structures, microRNA target sites, and developmental enhancers. Our results show that overlapping functional elements are common in mammalian genes, despite the vast genomic landscape.

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Mutations of LRTOMT, a fusion gene with alternative reading frames, cause nonsyndromic deafness in humans

Cited by 62 publications

References 30 publications

Screening of 38 Genes Identifies Mutations in 62% of Families with Nonsyndromic Deafness in Turkey

Screening of 38 Genes Identifies Mutations in 62% of Families with Nonsyndromic Deafness in Turkey

TFG, a target of chromosome translocations in lymphoma and soft tissue tumors, fuses to GPR128 in healthy individuals

Locating protein-coding sequences under selection for additional, overlapping functions in 29 mammalian genomes

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