| Human Molecular Genetics | Pages |
©1999 Oxford University Press |
Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families
Introduction
Results
Identification of two non-overlapping DFNA2 candidate regions
Physical map
EST analysis
Mutation analysis of KCNQ4
Discussion
Materials And Methods
DFNA2 families
Microsatellite marker typing
YACs, BACs and PACs
Mutation analysis
Acknowledgements
References
Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families
Received March 4, 1999; Revised and Accepted April 22, 1999
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.
INTRODUCTION
Hearing impairment is one of the most genetically heterogeneous hereditary diseases. Currently, >40 loci for hearing loss have been found in man and 11 genes have been identified (1-12). For some of these genes, their function in the cochlea is clear. A good example of such a gene is TECTA (4), a gene encoding an extracellular matrix protein that is a major structural component of the tectorial membrane. For other genes, such as DFNA5 (10) and COCH (11), the function is unknown. Continuously updated lists of loci and genes responsible for hearing loss can be found in the Hereditary Hearing Loss Homepage (http://dnalab-www.uia.ac.be/dnalab/hhh/ ).
We previously found linkage between markers of chromosome 1p34 and autosomal dominant hearing loss in two extended families originating from Indonesia and the USA (13). This locus was named DFNA2. Later, linkage to the DFNA2 region was found in three additional families from Belgium and The Netherlands (14). Under the assumption that a single gene was responsible for the hearing loss in these families, we delineated a candidate region of 1.25 Mb containing the DFNA2 gene (14).
Xia et al. (12) recently reported the identification of a novel connexin gene, GJB3, and detected mutations in two small Chinese families with autosomal dominant hearing loss. As this gene mapped to chromosome 1p34, we examined it for mutations in patients of our five autosomal dominant non-syndromic hearing impairment (DFNA2) families, but no mutations could be detected (15).
Recently, Kubisch et al. (16) identified a novel member of the KCNQ voltage-gated K+ channel family (KCNQ4). Two other K+ channel subunits, KCNQ1 (or KvLQT1) and KCNE1 (or minK or Isk), have been implicated in hereditary hearing loss. Heterozygous mutations in either gene lead to a form of cardiac arrhythmia known as long QT syndrome (LQTS) (17,18). Homozygous mutations result in a combination of LQTS and deafness called Jervell and Lange-Nielsen syndrome (19). As the KCNQ4 gene was mapped to chromosome 1p34 in the same region as DFNA2, a KCNQ4 mutation search was performed in patients with hereditary hearing impairment and a mutation was found in three patients from a small French family with non-syndromic autosomal dominant hearing loss (16).
The KCNQ4 gene encodes a protein of 695 amino acid residues. The homology with other members of the KCNQ family ranges from 37 to 44% at the amino acid level. At the genomic DNA level, KCNQ4 is organized in 14 exons. The KCNQ4 protein contains six domains that span the cellular membrane, and a P-loop domain which forms the K+-selective channel pore. The fourth transmembrane domain contains the voltage sensor, which is responsible for the electrically driven conformational change that leads to channel opening. Functional channels are formed by a tetrameric assembly of KCNQ4 subunits, typically in homotetrameric form, but heterotetrameric co-assembly of different members is allowed (20-22). It has been shown by in situ hybridization that KCNQ4 is expressed in the outer, but not in the inner, sensory hair cells of the cochlea (16). No expression was found in the stria vascularis. It was suggested that KCNQ4 is responsible for recycling K+ ions after stimulation of the hair cell (16).
In this study, we analysed new genetic markers to further refine the linkage interval defined by the five DFNA2 families. Surprisingly, we found that the candidate regions delineated by key recombinants of the Indonesian and Dutch family 1 were mutually exclusive, whereas the candidate regions of the three remaining DFNA2 families overlap with both. These data suggest that two different genes on 1p34 are responsible for the hearing loss in our set of families. The KCNQ4 gene was shown to be located in the candidate region of all DFNA2 families except the Indonesian one. Unique mutations were identified in four families, but in the Indonesian family we were unable to detect a mutation. Previously, we had analysed the coding region of GJB3 in this family, but did not find any mutation (15). Although the promotor or regulatory sequences of connexin (Cx)31 may contain a mutation, these data suggest that three deafness genes, GJB3, KCNQ4 and a currently unidentified gene in the Indonesian family, lie in close proximity on chromosome 1p34.
RESULTS
Identification of two non-overlapping DFNA2 candidate regions
To further refine the DFNA2 candidate region, we analyzed 16 additional markers from the DFNA2 region in five DFNA2 families. These markers are present on the Généthon (http://www.genethon.fr/ ), CHLC (http://www.chlc.org/ ) and Whitehead (http://www-genome.wi.mit.edu/ ) maps. As demonstrated in Figure 1, the candidate region of Dutch family 1 (between D1S2892 and D1S2645) and the Indonesian candidate region (between D1S201 and AFMB-338WG5) do not overlap. The remaining three candidate regions determined by recombinants of the US, Dutch family 2 and the Belgian families overlap with both candidate regions. These data suggest that at least two different deafness genes are present on chromosome 1p34.
Figure 1. Graphical representation of the candidate regions in the different DFNA2 families. Black boxes indicate the DFNA2 candidate region as determined by the recombinants in each family. On the left the markers used in the analysis are ordered from telomere to centromere (not drawn to scale) and the two non-overlapping candidate regions are marked with grey boxes. No recombinants were found with these markers in the Belgian family. The positions of the KCNQ4 and GJB3 genes are indicated with arrows.
Physical map
By screening the Whitehead database electronically with markers D1S432, MYCL1 and D1S193, we selected 19 YAC clones (Whitehead database contig WC 1.10). A commercially available PAC and BAC library suitable for PCR analysis (Human PAC Library PAC-6539 and Human BAC Library BAC-5331; Genome Systems) was used to identify PACs and BACs from the Dutch 1 candidate region. Additional PACs (635E8, 619B5 and 739H11) were selected from the chromosome 1 PAC contigs 351 and 430 from the Sanger Centre (http://www.sanger.ac.uk ). We prepared DNA from all these clones and used STS content determination by PCR to construct a contig consisting of 19 YACs, two BACs and 22 PACs. The YAC contig spans D1S432 to GATA-13B08 (Fig. 2a); the BAC-PAC contig spans a region from D1S2892 to D1S2645 (Fig. 2b). The order of the genetic markers determined by PCR on the YAC-BAC-PAC map was consistent with the order of these markers determined by haplotype analysis of our DFNA2 families. However, when our order of genetic markers was compared with the Généthon map, a few differences were found. Based on their position on the YAC contig, we place genetic marker D1S2645 telomeric, and markers D1S2632, D1S2861 and D1S2722 centromeric, to D1S193, whereas this is the opposite on the Généthon map. The Généthon order of genetic markers would introduce several internal deletions in clones from our YAC map and is, therefore, less likely. Also, we map marker D1S2743 centromeric relative to D1S432, physically as well as genetically, whereas on the Généthon map D1S2743 is telomeric to D1S432. However, Généthon's locus order for D1S432 and D1S2743 would result in double recombinants in the haplotypes of the DFNA2 families, whereas no double recombinants are seen using our locus order.
a
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b
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Figure 2. (a) YAC contig of the region between D1S432 and GATA-13B08. (b) BAC/PAC contig of the region between D1S2892 and GATA-P32043. Horizontal lines represent the YACs, PACs and BACs. Black dots indicate a positive PCR signal for the marker on the respective clone. The top bars represent chromosome 1p34. One asterisk (*) indicates that the marker is a genetic marker, two asterisks (**) indicates that the marker is an STS and three asterisks (***) indicate that the marker is an EST. The centromeric part of the candidate region for the Indonesian family is indicated by a grey box, whereas the candidate region for Dutch family 1 is indicated by a black box.
Apparently, a gap is present between markers cda0jd03 and stSG425 in the YAC contig as well as in the BAC-PAC contig. Also, the Whitehead YAC contig WC 1.10 contains this gap, suggesting that a non-clonable DNA sequence is present in this region. To determine the size of the gap, we used FIBER-FISH analysis with flanking PACs 257P5 and 171K17 as probes. This analysis indicated that the gap is <50 kb (data not shown).
EST analysis
A total of 62 ESTs were typed against our YAC, BAC and PAC contigs by PCR. We screened the Human Gene Map (http://www.ncbi.nlm.nih.gov/SCIENCE96/ ) electronically with markers D1S2892 and D1S2706, which returned 58 ESTs. The Whitehead map returned four ESTs (WI-6856, stSG10093, WI-2063 and WI-10754) that were not present in the Human Gene Map. All of these ESTs were PCR amplified on the available YACs, BACs and PACs from the DFNA2 candidate region. Forty-four ESTs could be mapped on the contigs (Fig. 2). Several of these mapped ESTs belong to known genes such as CLN1, iPAB, ADE2, guanylin precursor, glucose transporter type 1, MYCL1, Zn-15-related zinc finger protein and collagen 9[alpha]2.
Mutation analysis of KCNQ4
To detect mutations in the KCNQ4 gene of DFNA2 patients, we PCR amplified and sequenced each of the 14 exons from one affected individual from all five DFNA2 families. In four families a mutation was found, but thorough sequencing of all 14 exons in several patients from the Indonesian family revealed no disease-causing mutation.
In the remaining four DFNA2 families, three missense mutations and one deletion were found (Table 1; Figs 3 and 4). These missense mutations substitute amino acids that are conserved in all KCNQ family members (Fig. 5). Two missense mutations (W276S and G285C) substitute amino acids located in the P-loop domain, whereas the G321S mutation is located in the S6 transmembrane domain of KCNQ4. In the Belgian family, a deletion of 13 bp between nucleotide positions 211 and 224 of the KCNQ4 cDNA sequence was found. This deletion results in a frameshift after Gly70 (FS71), followed by 63 novel amino acids and a premature stop codon at amino acid position 134. The mutation is expected to yield a KCNQ4 protein that is truncated before the first transmembrane region (Fig. 3).
Figure 3. Graphical representation of the KCNQ4 voltage gated K+ channel. The six transmembrane domains (S1-S6) as well as the P-loop, located between S5 and S6, are indicated. The voltage sensor region is responsible for channel activation. All five currently known KCNQ4 mutations are indicated. The G285S mutation has been described previously by Kubisch et al. (16).
Table 1. KCNQ4 mutations in DFNA2 families
| Family | Protein change | Protein domain | DNA change | Exon |
| US | G285C | Pore region | 853G->T | 6 |
| Belgian | FS71 | N-terminal cytoplasmatic | 211del13 | 1 |
| Dutch 1 | W276S | Pore region | 827G->C | 5 |
| Dutch 2 | G321S | S6 transmembrane domain | 961G->A | 7 |
For the missense mutations, we developed a diagnostic test based on PCR amplification and restriction enzyme digestion (Table 2). The 13 bp deletion was detected on the basis of size and the presence of heteroduplex bands on polyacrylamide gels. We used these assays to examine the remaining members in each family. All patients were heterozygous for the mutation found in their respective family, whereas this mutation was not found in any of the unaffected individuals. Previously, we identified one phenocopy in the Belgian family and two phenocopies in Dutch family 1 by haplotype analysis (14). The absence of the mutation in these patients was confirmed by the mutation assays.
Table 2. Fast assays to detect KCNQ4 mutations by PCR amplification and restriction enzyme digestion
| Mutation | Primers | Primer sequence | Restriction enzyme |
| 853G->T | F6Ma | 5[prime]-CCA GAT TAC ATT GAC AAC CAG CT-3[prime] | AluI cuts mutant |
| R6 | 5[prime]-ATG TGT GAC AGG GGTGA GC-3[prime] | ||
| 211del13 | F1 | 5[prime]-CAT GCG TCT CTG AGC GCC CCG AGC-3[prime] | None |
| R1i | 5[prime]-CAC GTT GTA GAC CCA GTT CTG CAG GC-3[prime] | ||
| 827G->C | F5Ma | 5[prime]-CCT ACG CCG ACT CGC TCT GAT C-3[prime] | MboI cuts mutant |
| R5 | 5[prime]-AGT CAC GAT GGG CAG ACC TCG-3[prime] | ||
| 961G->A | F7 | 5[prime]-AAG GAT GGG GAC ACC CTT GC-3[prime] | AluI cuts mutant |
| R7 | 5[prime]-ACA CAG GGT TGA CAC ACC-3[prime] |
For the 211del13 mutation, the analysis is based on a difference in length.
DISCUSSION
Recently, a mutation in a novel K+ channel (KCNQ4) was found in a small French family with autosomal dominant hearing loss (16). We performed mutation analysis of the KCNQ4 gene in patients from five large DFNA2 families and identified three missense mutations and a 13 bp deletion in four of these families. No mutation was found in a fifth, Indonesian family.
The G285C mutation found in the US family alters the same glycine residue as the mutation that was found previously in the French family, where it was mutated to a serine (16). This highly conserved glycine is the first residue of an important GYGD motif found in K+ channels of different classes and species (Fig. 5). It has been shown that the GYGD motif is absolutely required for K+ selectivity by Heginbotham et al. (23), who expressed the Drosophila Shaker K+channel gene in Xenopus oocytes. They showed that substitution of this glycine by cysteine or serine keeps the channel conductance intact, but abolishes the K+selectivity of the pore. Whereas wild-type Shaker channels are highly selective for potassium, these mutant channels show no preference for K+ over other ions, such as Na+, Cs+ or NH4+ (23). Remarkably, similar experiments with the human KCNQ4 gene containing the G285C mutation indicated that the mutation abolishes the K+ current completely (16). In addition, substitution of this glycine by a serine in human KCNQ1 results in no detectable current after expression in Xenopus oocytes (24). Although there is little doubt that the G285C mutation found in the US DFNA2 family strongly interferes with KCNQ4 function, the biophysical nature of this defect, either loss of conductance or loss of ion selectivity, remains to be determined.
The W276S mutation, found in Dutch family 1, is also located in the P-loop domain of KCNQ4. Trp276 is conserved in many different K+ channels (Fig. 5). Perozo et al. (25) described a mutation in the conserved neighbouring tryptophan residue in the Drosophila Shaker channel gene, which completely abolishes ion conduction. The molecular model of the pore region provides additional evidence for the functional importance of these two adjacent tryptophan residues in the pore region (26). As this model indicates that the tryptophan and the tyrosine residues of the P-loop domain are involved in holding the pore open at a proper diameter, a strong effect of the W276S mutation on KCNQ4 function is likely.
The third missense mutation, found in Dutch family 2 (G321S), is located in the sixth transmembrane domain of KCNQ4. As this residue is conserved between KCNQ family members (Fig. 5) and as mutations in the S6 transmembrane region of KCNQ1 have been described in families with LQTS (17,27,28), it is likely that this mutation is disease-causing in Dutch family 2.
The fourth mutation (211del13), found in the Belgian DFNA2 family, results in a protein that is truncated before the first transmembrane domain. The pathogenic mechanism of this deletion in KCNQ4 remains unclear. Haploinsufficiency is a possibility as this mechanism has been described for mutations in the HERG K+ channel gene (KCNH2) leading to LQTS (29).
Most mutations found in K+ channels, including the three missense mutations in KCNQ4 described here, are missense mutations. A functional K+ channel consists of four subunits. The presence of a heterozygous mutation that leads to 50% defective subunits causes only 1/16 of all tetramers to be functional. Therefore, a dominant-negative effect has been proposed for many pathogenic missense mutations in other K+ channels. Using mutant constructs, a dominant-negative effect of missense mutations in other KCNQ family members has been demonstrated in a few cases (16,21,24).
The discovery of four different mutations in four DFNA2 families with many patients provides opportunities for a genotype-phenotype correlation study. The phenotype of the three DFNA2 families carrying a missense mutation is very similar, even after statistical analysis of the audiograms (see Materials and Methods). However, the deletion mutation in the Belgian family leads to a slightly different type of hearing impairment that can only be distinguished after statistical analysis of the audiograms. As different statisticians performed the statistical analyses using different methods, a detailed genotype-phenotype correlation will have to await a joint analysis of all families. In addition, electrophysiological experiments will be needed to confirm the pathogenic effect for each of the mutations and might give insight into the underlying molecular mechanisms.
KCNQ1 and KCNQ4 are both expressed in the heart as well as in the cochlea (16,17). The fact that KCNQ4 expression in the heart is low might explain why heart problems were not reported in association with hearing impairment in the DFNA2 families. KCNQ1 and KCNQ4 have different expression patterns in the cochlea. As KCNQ1 is expressed in the stria vascularis and KCNQ4 in the outer hair cells, they most likely have very different functions, possibly explaining the difference in inheritance pattern of deafness seen in families with KCNQ1 and KCNQ4 mutations.
One of the advantages of ion channels is that they can be expressed with relative ease in Xenopus laevis oocytes and, also, the effect of drugs on the function of the channel can be investigated in vitro. For LQTS, the identification of the responsible genes has already led to the investigation of a possible drug therapy (30,31). The further study of KCNQ4 mutations may also lead to more insights into its role in the hearing process and possibly to new therapies for hearing loss.
Figure 4. Mutation analysis of KCNQ4 in four DFNA2 families. The nucleotide sequence analysis of a heterozygote patient and a control is given, as well as a PCR assay (for details see text and Table 2). Lane 1, DNA size standard; lane 2, patient; lane 3, control; lane 4, blank. A, US family; B, Dutch family 1; C, Dutch family 2; D, Belgian family.
Figure 5. Alignment of the amino acid sequences of the P-loop domain and the S6 transmembrane region of the KCNQ4 gene with other KCNQ family members, as well as a few selected members of other K+ channel families. The alignment is based on the work of Doyle et al. (26). The amino acids substituted by missense mutations are indicated in bold. mSlo, Mus musculus, PIR accession no. A48206, KCNM family; herg, Homo sapiens, PIR accession no. I38465, KCNH family; Rat.RK5 (Kv4.2), Rattus norvegicus, GenBank accession no. M59980, KCNH family; KcsA, Streptomyces lividans, PIR accession no. S60172; Shaker, Drosophila melanogaster, PIR accession no. S00479, KCNA family; KCNQ1 (KvLQT1), Homo sapiens, PIR accession no. 3953684, KCNQ family; KCNQ2, Homo sapiens, PIR accession no. 4028015, KCNQ family; KCNQ3, Homo sapiens, PIR accession no. 2801450, KCNQ family; KCNQ4, Homo sapiens, PIR accession no. 4262539, KCNQ family.
MATERIALS AND METHODS
DFNA2 families
We analysed five extended families with autosomal dominant progressive hearing loss linked to the DFNA2 region. All five families have been reported on before (13,14,32). The hearing loss in all five families is progressive, starts with high frequencies, has a sensorineural origin and is non-syndromic. However, subtle differences between the phenotypes of patients from the different families are present. The age at onset is clearly after 10 years for the Indonesian family, while in the other families children <10 years of age with high frequency hearing loss have been found (33). In addition, the hearing impairment in the Indonesian family is reported to be more variable compared with that of the other families (34).
Statistical analysis of the audiometric data showed a difference between the Belgian family and the rest of the families. In the Belgian family the average progression of hearing loss for high frequencies is about five times faster than progression for low frequencies (unpublished data). For the other families, the average rate of hearing loss is ~1 dB/year for all frequencies, but the onset of hearing loss is earlier for high frequencies compared with low frequencies (32-32).
Microsatellite marker typing
Genomic DNA was isolated from peripheral blood samples by standard techniques. PCR and electrophoresis were performed as described with the following microsatellite markers: D1S201, D1S255, D1S2783, D1S432, D1S1591, AFMB338WG5, D1S2657, D1S2892, D1Z11, MYCL1, D1S1598, GATA-P18584, D1S2743, D1S2706, D1S2645, D1S193, D1S2861, D1S2632, AFMA-289 and D1S2722. PCR conditions and details for all these markers can be found in the Genome Database (http://gdbwww.gdb.org/ ).
YACs, BACs and PACs
YAC clones were grown in AHC medium for 48 h and total yeast DNA was extracted using standard methods. BAC and PAC clones were grown in LB medium and their DNA was isolated using the Qiagen tip 100 kit (Qiagen, Hilden, Germany). PCR amplification of the markers from the DFNA2 candidate region on YAC, BAC and PAC DNA was done using standard methods. PCR products were separated on 1% agarose gels and stained with ethidium bromide.
Mutation analysis
Mutation analysis was performed by genomic exon sequencing. PCR was carried out using primers flanking the 14 KCNQ4 exons (16). Reaction conditions were optimized for the different primer sets. As exon 1 has a high GC content at the 5[prime] end, it has been amplified in two overlapping parts with internal cDNA primers using the Advantage-GC cDNA PCR kit (Clontech, Palo Alto, CA). PCR products were purified with the PCR Quick purification kit (Qiagen).
Sequence analysis using one of the amplification primers was performed with Big dye terminator sequencing kits on an ABI-377 synthesizer (Perkin Elmer, Warrington, UK). Fast assays were developed for all mutations. If the mutation destroyed or created a restriction site, amplification of the respective KCNQ4 exon was followed by digestion with the respective restriction enzyme. If no restriction site was created or destroyed by the mutation, we designed a modified primer giving rise to a novel restriction site as described previously (35). Table 2 lists the primers and restriction enzymes used to identify the different mutations. Fragments were separated on 2% agarose or 12% polyacrylamide gels.
ACKNOWLEDGEMENTS
We thank T.J. Jentsch, C. Kubisch and B. Schroeder for help and unpublished information, and D. Snyders for helpful discussions. This study was supported by a grant from the University of Antwerp, a grant from the Flemish Fonds voor Wetenschappelijk Onderzoek (FWO), by NIH grants R01 DC02942-03 (S.D.S.) and R01DCO2842 (R.J.H.S.) and by RCMI grants P20RR11145-01 (S.B.) and G12RR03026 (S.B.). P.V.H. holds a pre-doctoral research position with the Vlaams Instituut ter Bevordering van het Wetenschappelijk-Technologisch Onderzoek in de Industrie (IWT) and G.V.C. holds a research position with the FWO.
REFERENCES
*The first two authors contributed equally to this work
+To whom correspondence should be addressed. Tel: +323 820 2670; Fax: +323 820 2566; Email: gvcamp{at}uia.ua.ac.be
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