Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families

Abstract

We have previously found linkage to chromosome 1p34 in five large families with autosomal dominant non-syndromic hearing impairment (DFNA2). In all five families, the connexin31 gene ( GJB3 ), located at 1p34 and responsible for non-syndromic autosomal dominant hearing loss in two small Chinese families, has been excluded as the responsible gene. Recently, a fourth member of the KCNQ branch of the K+channel family, KCNQ4, has been cloned. KCNQ4 was mapped to chromosome 1p34 and a single mutation was found in three patients from a small French family with non-syndromic autosomal dominant hearing loss. In this study, we have analysed the KCNQ4 gene for mutations in our five DFNA2 families. Missense mutations altering conserved amino acids were found in three families and an inactivating deletion was present in a fourth family. No KCNQ4 mutation could be found in a single DFNA2 family of Indonesian origin. These results indicate that at least two and possibly three genes responsible for hearing impairment are located close together on chromosome 1p34 and suggest that KCNQ4 mutations may be a relatively frequent cause of autosomal dominant hearing loss.

Reconstitution of Muscarinic Modulation of the KCNQ2/KCNQ3 K+Channels That Underlie the Neuronal M Current

“…If neuronal M current indeed does result from KCNQ2 and KCNQ3 channel expression, then the dysfunction seen in individuals with non-or weakly functional mutant forms of these channels demonstrates that the M current plays an important stabilizing role in the nervous system. Finally, mutations in the newest member of this gene family to be identified, KCNQ4, result in a distinct syndrome of human deafness (Coucke et al, 1999;Kubisch et al, 1999).…”

“…For example, this heterogeneity may explain the observation of M channels in the same cell with different unitary conductances and sensitivities to intracellular Ca 2ϩ (Stansfeld et al, 1993;Selyanko and Brown, 1996). Furthermore, in different cell types the subunit arrangements may differ, and perhaps KCNQ4 subunits are included as well (Coucke et al, 1999;Kubisch et al, 1999). Recently, it has been suggested that some of the channels underlying M-like currents in a neuroblastoma cell line, but not in rat or mouse sympathetic neurons, are formed from Erg1 channel subunits, as well as others formed by KCNQ2 and KCNQ3 .…”

Identification of a novel in-frame deletion in KCNQ4 (DFNA2A) and evidence of multiple phenocopies of unknown origin in a family with ADSNHL

“…15 To date, 16 mutations in KCNQ4 are associated with ADSNHL, including 11 missense, 11,12,15-24 1 nonsense, 15 1 splice-site mutation 21 and 3 deletions. 17,19,20 Of the 11 missense mutations reported, 6 are found in the P-loop and cause early-onset allfrequency hearing loss.…”

“…The first described deletion, c.211del13, was found in a Belgian family and results in a frameshift after the G70 residue leading to a premature stop codon at amino-acid position 134. 17 The second KCNQ4 deletion, c.211delC, was found in a Japanese family and is predicted to generate a truncated protein before the first transmembrane domain. 20 Generally, missense mutations in KCNQ4 have been associated with more severe, earlier-onset, all-frequency SNHL, while deletions are reported to cause a milder phenotype characterized by a later age of onset affecting only high frequencies.…”

Benign familial neonatal convulsions (BFNC) resulting from mutation of the KCNQ2 voltage sensor

“…[15][16][17] Mutations in KCNQ4, which is expressed in sensory outer hair cells of the cochlea, cause an autosomal dominant non-syndromic deafness (DFNA2). [18][19][20] Although several mutations affecting the trans-membrane domains and the pore region have been described in these syndromes none of them involve the S4 domain (Figure 2c). R214W represents the first description of a mutation involving the K + channel voltage sensor in a human disease associated with altered regulation of cellular excitability.…”