Noncoding microdeletion in mouse<i>Hgf</i>disrupts neural crest migration into the stria vascularis, reduces the endocochlear potential and suggests the neuropathology for human nonsyndromic deafness DFNB39

Morell, Robert J.; Olszewski, Rafal T.; Tona, Risa; Leitess, Samuel; Schultz, Julie M.; Thomason, Elizabeth J.; Whitley, Brittany N.; Hill, Connor; Saunders, Thomas L.; Starost, Matthew F.; Fitzgerald, Tracy S.; Wilson, Elizabeth A.; Ohyama, Takahiro; Friedman, Thomas B.; Hoa, Michael

doi:10.1101/778365

Cited by 2 publications

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“…The c.482+1986_1988del variant identified in this study has been previously reported to cause prelingual, profound deafness (DFNB39, MIM 608265) [43]. A Hgf 10 bp deletion in homozygous mutant mice, which fully encompasses the 3 bp deletion in humans, also displayed profound hearing loss at 4 weeks age (Figure 3(d)) [55]; Hgf 10 bp deletion in homozygous mice causes low expression of Hgf in the cochlea, which leads to developmental defect of the stria vascularis and reduced endocochlear potential in the cochlea [55]. The 3 bp deletion in the intronic region possibly has a similar mechanism to cause hearing loss.…”

Section: Discussionsupporting

confidence: 56%

Next-Generation Sequencing Identifies Pathogenic Variants in HGF, POU3F4, TECTA, and MYO7A in Consanguineous Pakistani Deaf Families

et al. 2021

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Background. Approximately 70% of congenital deafness is attributable to genetic causes. Incidence of congenital deafness is known to be higher in families with consanguineous marriage. In this study, we investigated the genetic causes in three consanguineous Pakistani families segregating with prelingual, severe-to-profound deafness. Results. Through targeted next-generation sequencing of 414 genes known to be associated with deafness, homozygous variants c.536del (p. Leu180Serfs ∗ 20) in TECTA, c.3719 G>A (p. Arg1240Gln) in MYO7A, and c.482+1986_1988del in HGF were identified as the pathogenic causes of enrolled families. Interestingly, in one large consanguineous family, an additional c.706G>A (p. Glu236Lys) variant in the X-linked POU3F4 gene was also identified in multiple affected family members causing deafness. Genotype-phenotype cosegregation was confirmed in all participating family members by Sanger sequencing. Conclusions. Our results showed that the genetic causes of deafness are highly heterogeneous. Even within a single family, the affected members with apparently indistinguishable clinical phenotypes may have different pathogenic variants.

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Section: Discussionsupporting

confidence: 56%

Next-Generation Sequencing Identifies Pathogenic Variants in HGF, POU3F4, TECTA, and MYO7A in Consanguineous Pakistani Deaf Families

et al. 2021

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“…Compensation for the loss of TBC1D24 in mouse may be provided by a paralog in the mouse genome or compensation by a gene involved in the same network or signaling pathway [ 63 ]. For example, a dominant variant of METTL13 ( DFNM1 ) completely suppresses recessive non-syndromic deafness DFNB26, associated with a variant of GAB2 with both genes functioning in the HGF/MET signaling pathway [ 64 , 65 , 66 ].…”

Section: Discussionmentioning

confidence: 99%

Mouse Models of Human Pathogenic Variants of TBC1D24 Associated with Non-Syndromic Deafness DFNB86 and DFNA65 and Syndromes Involving Deafness

Tona

López

Fenollar–Ferrer

et al. 2020

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Human pathogenic variants of TBC1D24 are associated with clinically heterogeneous phenotypes, including recessive nonsyndromic deafness DFNB86, dominant nonsyndromic deafness DFNA65, seizure accompanied by deafness, a variety of isolated seizure phenotypes and DOORS syndrome, characterized by deafness, onychodystrophy, osteodystrophy, intellectual disability and seizures. Thirty-five pathogenic variants of human TBC1D24 associated with deafness have been reported. However, functions of TBC1D24 in the inner ear and the pathophysiology of TBC1D24-related deafness are unknown. In this study, a novel splice-site variant of TBC1D24 c.965 + 1G > A in compound heterozygosity with c.641G > A p.(Arg214His) was found to be segregating in a Pakistani family. Affected individuals exhibited, either a deafness-seizure syndrome or nonsyndromic deafness. In human temporal bones, TBC1D24 immunolocalized in hair cells and spiral ganglion neurons, whereas in mouse cochlea, Tbc1d24 expression was detected only in spiral ganglion neurons. We engineered mouse models of DFNB86 p.(Asp70Tyr) and DFNA65 p.(Ser178Leu) nonsyndromic deafness and syndromic forms of deafness p.(His336Glnfs*12) that have the same pathogenic variants that were reported for human TBC1D24. Unexpectedly, no auditory dysfunction was detected in Tbc1d24 mutant mice, although homozygosity for some of the variants caused seizures or lethality. We provide some insightful supporting data to explain the phenotypic differences resulting from equivalent pathogenic variants of mouse Tbc1d24 and human TBC1D24.

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Noncoding microdeletion in mouseHgfdisrupts neural crest migration into the stria vascularis, reduces the endocochlear potential and suggests the neuropathology for human nonsyndromic deafness DFNB39

Abstract: 1 stria vascularis, reduces the endocochlear potential and suggests the 2 neuropathology for human nonsyndromic deafness DFNB39 3 Abbreviated title: Mouse model of HGF DFNB39 deafness.

Cited by 2 publications

References 52 publications

Next-Generation Sequencing Identifies Pathogenic Variants in HGF, POU3F4, TECTA, and MYO7A in Consanguineous Pakistani Deaf Families

Next-Generation Sequencing Identifies Pathogenic Variants in HGF, POU3F4, TECTA, and MYO7A in Consanguineous Pakistani Deaf Families

Mouse Models of Human Pathogenic Variants of TBC1D24 Associated with Non-Syndromic Deafness DFNB86 and DFNA65 and Syndromes Involving Deafness

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