Mapping of a new autosomal dominant nonsyndromic hearing loss locus (DFNA30) to chromosome 15q25-26

Mangino, Massimo; Flex, Elisabetta; Capon, Francesca; Sangiuolo, Federica; Carraro, Edoardo; Gualandi, Francesca; Mazzoli, Manuela; Novelli, Giuseppe; Dallapiccola, Bruno

doi:10.1038/sj.ejhg.5200707

Cited by 11 publications

(9 citation statements)

References 21 publications

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“…However, the exact pathway and the role in the pathogenesis of otosclerosis remains unclear. Previous studies have also indicated a role for ACAN in hearing disorders in human (Dawson et al 2018;Hoffmann et al 2016a;Mangino et al 2001). In addition mice with mutant aggrecan show hearing loss (Yoo et al 1991), proving the importance of normal aggrecan expression in hearing.…”

Section: Discussionmentioning

confidence: 89%

“…For otosclerosis, it became a gene of interest when the OTSC1 locus was identified at 15q25-q26 (Tomek et al 1998). A locus for autosomal dominant hearing loss, at chromosomal location 15q25-26, was found in proximity of the ACAN gene, overlapping with the OTSC1 locus (Mangino et al 2001). A genome-wide association study into age-related hearing impairment (ARHI) showed a genome-wide significant association signal in variants close to the ACAN gene (Hoffmann et al 2016b).…”

Section: Introductionmentioning

confidence: 99%

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A wide range of protective and predisposing variants in aggrecan influence the susceptibility for otosclerosis

et al. 2021

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In this study we investigated the association of ACAN variants with otosclerosis, a frequent cause of hearing loss among young adults.We sequenced the coding, 5'-UTR and 3'-UTR regions of ACAN in 1497 unrelated otosclerosis cases and 1437 matched controls from six different subpopulations. The association between variants in ACAN and the disease risk was tested through single variant and gene-based association tests.After correction for multiple testing, 14 variants were significantly associated with otosclerosis, ten of which represented independent association signals. Eight variants showed a consistent association across all subpopulations. Allelic odds ratios of the variants identified four predisposing and ten protective variants. Gene-based tests showed association of very rare variants in the 3'-UTR with the phenotype.The associated exonic variants are all located in the CS domain of ACAN and include both protective and predisposing variants with a broad spectrum of effect sizes and population frequencies. This includes variants with a strong effect size and low frequency, typical for monogenic diseases, to low effect size variants with high frequency, characteristic for common complex traits. This single-gene allelic spectrum with both protective and predisposing alleles is unique in the field of complex 4 diseases. In conclusion, these findings are a significant advancement to the understanding of the etiology of otosclerosis.

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Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

A wide range of protective and predisposing variants in aggrecan influence the susceptibility for otosclerosis

et al. 2021

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“…There are 65 annotated DFNB48 candidate genes between these two markers of which NR2E3, MYO9A, BBS4, and TMC3 (bold) are discussed b does not overlap with the position of DFNB16, which has been identified as STRC (Campbell et al 1997;Verpy et al 2001), thus distinguishing DFNB48 as a unique locus. Autosomal dominant nonsyndromic hearing loss, DFNA30, delimited by markers D15S151 (82.28 cM) and D15S130 (100.59 cM) is also present on chromosome 15q25-q26 and has been mapped in a fourgeneration Italian family in which members have progressive hearing loss (Mangino et al 2001). The critical region of DFNB48 does not overlap with the DFNA30 locus.…”

Section: Discussionmentioning

confidence: 99%

DFNB48, a new nonsyndromic recessive deafness locus, maps to chromosome 15q23-q25.1

Ahmad

Khan

et al. 2005

Hum Genet

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Nonsyndromic deafness locus (DFNB48) segregating as an autosomal recessive trait has been mapped to the long arm of chromosome 15 in bands q23-q25.1 in five large Pakistani families. The deafness phenotype in one of these five families (PKDF245) is linked to D15S1005 with a lod score of 8.6 at theta=0, and there is a critical linkage interval of approximately 7 cM on the Marshfield human genetic map, bounded by microsatellite markers D15S216 (70.73 cM) and D15S1041 (77.69 cM). MYO9A, NR2E3, BBS4, and TMC3 are among the candidate genes in the DFNB48 region. The identification of another novel nonsyndromic recessive deafness locus demonstrates the high degree of locus heterogeneity for hearing impairment, particularly in the Pakistani population.

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“…Human SAXO2 is located on 15q25.2 (Table 1), near several sensorineural deafness loci including DFNA30 (gene unknown) [85], DFNA68 ( HOMER ) [86,87], DFNB48 ( CIB2 ) [88,89], and OTSC1 [90]. SHIELD reports that SAXO2 maps to the DFNA30 locus.…”

Section: Resultsmentioning

confidence: 99%

“…SHIELD reports that SAXO2 maps to the DFNA30 locus. The critical region for DFNA30 lies between markers D15S151 and D15S130 (GRCh38:15:87053920-94168232) with a maximum LOD score for marker D15S1004 [85]. However, current genomic coordinates for SAXO2 (GRCh38:15:82262818-82284927) place it outside the DFNA30 critical interval, 4.8 MB away from the closest marker D15S151 and 11.5 MB away from D15S1004.…”

Section: Resultsmentioning

confidence: 99%

Regionalized protein localization domains in the zebrafish hair cell kinocilium

Erickson

Biggers

Williams

et al. 2023

Preprint

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Sensory hair cells are the receptors for auditory, vestibular, and lateral line sensory organs in vertebrates. These cells are distinguished by "hair"-like projections from their apical surface collectively known as the hair bundle. Along with the staircase arrangement of actin-filled stereocilia, the hair bundle features a single, non-motile, true cilium called the kinocilium. The kinocilium plays important roles in hair bundle development and the mechanics of sensory detection. To understand more about kinocilial development and structure, we performed a transcriptomic analysis of zebrafish hair cells looking for cilia-associated genes that have yet to be characterized in hair cells. Here, we focus on three such genes - ankef1a, odf3l2a, and saxo2 - because the human or mouse orthologs are either associated with sensorineural hearing loss or are located near un-characterized deafness loci. We made transgenic fish that express fluorescently-tagged versions of their proteins, demonstrating their localization to the kinocilia of zebrafish hair cells. Furthermore, we find that Ankef1a, Odf3l2a, and Saxo2 exhibit distinct localization patterns along the length of the kinocilium. Lastly, we report a novel overexpression phenotype for Saxo2. Overall, these results suggest that the hair cell kinocilium is regionalized along its proximal-distal axis and set the groundwork to understand the role of these kinocilial proteins in hair cell structure and function.

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Mapping of a new autosomal dominant nonsyndromic hearing loss locus (DFNA30) to chromosome 15q25-26

Cited by 11 publications

References 21 publications

A wide range of protective and predisposing variants in aggrecan influence the susceptibility for otosclerosis

A wide range of protective and predisposing variants in aggrecan influence the susceptibility for otosclerosis

DFNB48, a new nonsyndromic recessive deafness locus, maps to chromosome 15q23-q25.1

Regionalized protein localization domains in the zebrafish hair cell kinocilium

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