Linkage Analysis of Progressive Hearing Loss in Five Extended Families Maps the DFNA2 Gene to a 1.25-Mb Region on Chromosome 1p

Camp, Guy Van; Coucke, Paul; Kunst, Henricus P. M.; Schatteman, Isabelle; Velzen, D. van; Marres, H.A.M.; Ewijk, M. van; Declau, Frank; Hauwe, P. van; Meyers, J.; Kenyon, J. B.; Smith, Shelley D.; Smith, Richard J.; Djelantik, Bulantrisna; Cremers, C.W.R.J.; Heyning, Paul Van de; Willems, P. J.

doi:10.1006/geno.1997.4624

Cited by 45 publications

(35 citation statements)

References 8 publications

(1 reference statement)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The locus for DFNA2 was originally linked to chromosome 1 by linkage analysis in Indonesian, American, and Dutch families with progressive hearing impairment (16) and localized to the 1p34 region by analysis in a Belgian family and two Dutch families (17). Subsequent to the cloning of the hK V 7.4 gene and mapping to 1p34 (2), mutant screenings of autosomal dominant progressive hearing loss patients, without linkage analysis, have identified mutations in European, American, Japanese, and Taiwanese families (Table 1).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Cellular and Molecular Mechanisms of Autosomal Dominant Form of Progressive Hearing Loss, DFNA2

Kim

Sihn

2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Despite advances in identifying deafness genes, determination of the underlying cellular and functional mechanisms for auditory diseases remains a challenge. Mutations of the human K ؉ channel hKv7.4 lead to post-lingual progressive hearing loss (DFNA2), which affects world-wide population with diverse racial backgrounds. Here, we have generated the spectrum of point mutations in the hKv7.4 that have been identified as diseased mutants. We report that expression of five point mutations in the pore region, namely L274H, W276S, L281S, G285C, and G296S, as well as the C-terminal mutant G321S in the heterologous expression system, yielded nonfunctional channels because of endoplasmic reticulum retention of the mutant channels. We mimicked the dominant diseased conditions by co-expressing the wild-type and mutant channels. As compared with expression of wild-type channel alone, the blend of wild-type and mutant channel subunits resulted in reduced currents. Moreover, the combinatorial ratios of wild type:mutant and the ensuing current magnitude could not be explained by the predictions of a tetrameric channel and a dominant negative effect of the mutant subunits. The results can be explained by the dependence of cell surface expression of the mutant on the wild-type subunit. Surprisingly, a transmembrane mutation F182L, which has been identified in a pre-lingual progressive hearing loss patient in Taiwan, yielded cell surface expression and functional features that were similar to that of the wild type, suggesting that this mutation may represent redundant polymorphism. Collectively, these findings provide traces of the cellular mechanisms for DFNA2.

show abstract

Section: Discussionmentioning

confidence: 99%

“…In humans, Kv7.4 is located on chromosome 1p34 (16,17). To date, as many as eight missense mutations have been reported resulting in seven specific point mutations, and in two extreme cases, there are frameshift mutations that end up with small truncated peptides (see Table 1).…”

mentioning

confidence: 99%

Cellular and Molecular Mechanisms of Autosomal Dominant Form of Progressive Hearing Loss, DFNA2

Kim

Sihn

2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…7A, and in complete agreement with the radiation hybrid studies, fluorescent signals corresponding to biotinylated FACE-1 clones were located on chromosome 1p34. A number of genes have been already mapped to this region, including those encoding CTP synthase, the subunit ␤2 of the proteasome, PAGA (proliferation-associated gene A), HDAC1 (histone deacetylase 1), as well as a two uncharacterized genes mutated in some cases of hereditary deafness (van Camp et al, 1997) and corneal distrophy (Shearman et al, 1996). However, no other metalloprotease genes have been previously found to map at this chromosome site.…”

Section: Chromosomal Mapping Of the Genes Encoding Human Face-1 And Fmentioning

confidence: 96%

Identification and Chromosomal Location of Two Human Genes Encoding Enzymes Potentially Involved in Proteolytic Maturation of Farnesylated Proteins

et al. 1999

View full text Add to dashboard Cite

“…DFNA2 is a locus responsible for autosomal-dominant, nonsyndromic hearing impairment in chromosome 1p34 (Coucke et al 1994;Van Camp et al 1997). Two hearing impairment genes, GJB3 and KCNQ4, have been identified in the DFNA2 locus (Kubisch et al 1999;Xia et al 1998).…”

Section: Introductionmentioning

confidence: 99%

A novel KCNQ4 one-base deletion in a large pedigree with hearing loss: implication for the genotype–phenotype correlation

et al. 2006

View full text Add to dashboard Cite

Autosomal-dominant, nonsyndromic hearing impairment is clinically and genetically heterogeneous. We encountered a large Japanese pedigree in which nonsyndromic hearing loss was inherited in an autosomal-dominant fashion. A genome-wide linkage study indicated linkage to the DFNA2 locus on chromosome 1p34. Mutational analysis of KCNQ4 encoding a potassium channel revealed a novel one-base deletion in exon 1, c.211delC, which generated a profoundly truncated protein without transmembrane domains (p.Q71fsX138). Previously, six missense mutations and one 13-base deletion, c.211_223del, had been reported in KCNQ4. Patients with the KCNQ4 missense mutations had younger-onset and more profound hearing loss than patients with the 211_223del mutation. In our current study, 12 individuals with the c.211delC mutation manifested late-onset and pure high-frequency hearing loss. Our results support the genotype-phenotype correlation that the KCNQ4 deletions are associated with later-onset and milder hearing impairment than the missense mutations. The phenotypic difference may be caused by the difference in pathogenic mechanisms: haploinsufficiency in deletions and dominant-negative effect in missense mutations.

show abstract

Linkage Analysis of Progressive Hearing Loss in Five Extended Families Maps the DFNA2 Gene to a 1.25-Mb Region on Chromosome 1p

Cited by 45 publications

References 8 publications

Cellular and Molecular Mechanisms of Autosomal Dominant Form of Progressive Hearing Loss, DFNA2

Cellular and Molecular Mechanisms of Autosomal Dominant Form of Progressive Hearing Loss, DFNA2

Identification and Chromosomal Location of Two Human Genes Encoding Enzymes Potentially Involved in Proteolytic Maturation of Farnesylated Proteins

A novel KCNQ4 one-base deletion in a large pedigree with hearing loss: implication for the genotype–phenotype correlation

Contact Info

Product

Resources

About