Met>Val substitution in a highly conserved region of the pro-alpha1(I) collagen C-propeptide domain causes alternative splicing and a mild EDS/OI phenotype.
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Alleles↗
Biomedical subjects
P J Coucke
Publications and source records attributed to P J Coucke.
Homozygosity mapping of a gene for arterial tortuosity syndrome to chromosome 20q13.
BACKGROUND: Arterial tortuosity syndrome (ATS) is an uncommon connective tissue disorder of unknown aetiology. The most prominent feature is tortuosity of the large arteries, but lengthening, stenosis, and aneurysm formation are also frequent. METHODS: We performed a genomewide screen by homozygosity mapping of three consanguineous multiplex families, two from Morocco, and one from Italy, which included 11 ATS patients. The two families from Morocco may possibly have a common ancestor. RESULTS: We mapped the ATS gene to chromosome 20q13. Recombinations within an extended haplotype of 11 microsatellite markers localised the ATS gene between markers D20S836 and D20S109, an interval of 9.5 cM. CONCLUSIONS: Cloning and completing functional and structural analysis of the ATS gene may provide new insights into the molecular mechanisms of elastogenesis.
Adolescent↗
Mutations in the KCNQ4 K+ channel gene, responsible for autosomal dominant hearing loss, cluster in the channel pore region.
The DFNA2 locus for autosomal dominant nonsyndromic hearing impairment on chromosome 1p34 contains at least 2 genes responsible for hearing loss, GJB3 and KCNQ4. GJB3 is a member of the connexin gene family and KCNQ4 is a voltage-gated potassium channel. KCNQ4 mutations were first found in a French family, and later also in a Belgian, an American and two Dutch families. Here we present the analysis of the GJB3 and KCNQ4 genes in a third Dutch family linked to DFNA2. No mutation was found in GJB3, but a missense mutation changing a conserved Leu residue into His (L274H) was found in the coding region of the KCNQ4 gene in all patients of this DFNA2 family. Examination of the position of all known KCNQ4 mutations showed a clustering of mutations in the pore region of the KCNQ4 gene, responsible for the ion selectivity of the channel. The clustering of mutations in this domain confirms its importance.
Amino Acid Sequence↗
Deafness linked to DFNA2: one locus but how many genes?
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5' Untranslated Regions↗
Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families.
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.
Amino Acid Sequence↗
Identification of two different mutations in the PDS gene in an inbred family with Pendred syndrome.
Recently the gene responsible for Pendred syndrome (PDS) was isolated and several mutations in the PDS gene have been identified in Pendred patients. Here we report the occurrence of two different PDS mutations in an extended inbred Turkish family. The majority of patients in this family are homozygous for a splice site mutation (1143-2A-->G) affecting the 3' splice site consensus sequence of intron 7. However, two affected sibs with non-consanguineous parents are compound heterozygotes for the splice site mutation and a missense mutation (1558T-->G), substituting an evolutionarily conserved amino acid. The latter mutation has been found previously in two Pendred families originating from The Netherlands, indicating that the 1558T-->G mutation may be a common mutation.
Base Sequence↗
Chromosomal mapping of two members of the human dynein gene family to chromosome regions 7p15 and 11q13 near the deafness loci DFNA 5 and DFNA 11.
We mapped expressed tagged sequences (ESTs) corresponding to two human dynein heavy chain genes: beta heavy chain of the outer dynein arm and heavy chain isotype 1B (DYH1B), by using somatic cell hybrids and radiation hybrid panels. The EST for the beta heavy chain of the outer dynein arm mapped to chromosome region 7p15, and the EST for DYH1B mapped to 11q13.5. Two loci for nonsyndromic forms of deafness, DFNA5 and DFNA11, have previously been mapped to these two chromosomal regions. Including the gene for the axonemal light chain, hp28, we have mapped three different dynein genes near loci for different forms of nonsyndromic deafness. The hypothesis that mutations in some dynein genes are associated with nonsyndromic deafness should now be tested.
Chromosome Mapping↗
Linkage analysis of progressive hearing loss in five extended families maps the DFNA2 gene to a 1.25-Mb region on chromosome 1p.
Thus far, 13 genes for autosomal dominant hearing loss have been localized to specific chromosomal regions, but none of the genes has been cloned. Only a single family has been linked to each of these loci, with the exception of DFNA2. DFNA2 was originally mapped in two extended families originating from Indonesia and the United States. In this study we report linkage to DFNA2 in three additional large families with autosomal dominant hearing loss from Belgium and The Netherlands. These five DFNA2 families show a similar progressive sensorineural hearing loss, starting in the high frequencies and also affecting the middle and low frequencies later in life. Combining the information from all linked families, the candidate region that is most likely to contain the DFNA2 gene was reduced to a 1.25-Mb region between markers D1S432 and MYCL1. Different haplotypes segregating with the hearing loss were found in all five families, suggesting that different mutations are present in the same gene. These results indicate that DFNA2 is most likely an important gene for autosomal dominant hearing loss.
Alleles↗
Complementary deoxyribonucleic acid cloning and characterization of a putative human axonemal dynein light chain gene.
Immotile Cilia Syndrome (ICS) is characterized by recurrent sinus and lung infections, bronchiectasis, and sperm immotility. Nasal cilia and sperm tails in patients with ICS exhibit a variety of ultrastructural defects, often including shortening or absence of the inner dynein arms. Immotile mutant strains of Chlamydomonas, a biflagellated algae, have ultrastructural defects similar to those seen in patients with this clinical disorder. Furthermore, splice-site mutations in the Chlamydomonas inner dynein arm gene (p28) are associated with impaired flagellar motility. We therefore hypothesized that the human homologue of the Clamydomonas dynein p28 gene would be an attractive candidate gene for patients with ICS. Accordingly, we cloned the full length complementary DNA (cDNA) and genomic clone by screening of appropriate libraries and databases, using the protein sequence of the Chlamydomonas p28 gene. The human homologue is encoded by a 921 bp transcript (accession no. AF006386) with an open reading frame of 257 amino acids. Using somatic cell and radiation hybrid panels, the hp28 gene was mapped to human chromosome 1p35.1. The hp28 cDNA probe hybridizes to sequences in all species on a zoo blot containing genomic DNA from yeast to human. Northern blot analysis reveals two hp28 gene transcripts, 0.9 and 2.5 kb, in many tissues. The 0.9 kb transcript is expressed at a 20-fold higher level than the 2.5-kb transcript in the testis. The entire gene is included in a 20-kb EcoRI genomic fragment and has 7 exons and 6 introns. Cloning of the hp28 cDNA and mapping of the intron-exon junctions should now make it possible to test whether a subset of ICS is a consequence of mutations in the human axonemal dynein light chain gene hp28.
Base Sequence↗
Mapping of the gene for X-linked liver glycogenosis due to phosphorylase kinase deficiency to human chromosome region Xp22.
X-linked liver glycogenosis (XLG) is a glycogenosis due to deficient activity of phosphorylase kinase (PHK) in liver. PHK consists of four different subunits, alpha, beta, gamma, and delta. Although it is unknown whether liver and muscle PHK subunits are encoded by the same genes, the muscle alpha subunit (PHKA) gene was a likely candidate gene for the mutation responsible for this X-linked liver glycogenosis as it was assigned to the X chromosome at q12-q13. Linkage analysis with X-chromosomal polymorphic DNA markers was performed in two families segregating XLG. First, multipoint linkage analysis excluded the muscle PHKA region as the site of the XLG mutation. Second, evidence was obtained for linkage between the XLG locus and DXS197, DXS43, DXS16, and DXS9 with two-point peak lod scores Zmax = 6.64, 3.75, 1.30, and 0.88, all at theta max = 0.00, respectively. Multipoint linkage results and analysis of recombinational events indicated that the mutation responsible for XLG is located in Xp22 between DXS143 and DXS41.
Chromosome Mapping↗
Linkage of DNA markers at Xq28 to adrenoleukodystrophy and adrenomyeloneuropathy present within the same family.
We present a large kindred that contained patients with either adrenoleukodystrophy (ALD) or adrenomyeloneuropathy (AMN). The pedigree clearly supported the X-linked mode of inheritance of the nonneonatal form of ALD/AMN. Analysis with DNA markers at Xq28 suggested segregation of both ALD and AMN with an identical haplotype. This indicated that nonneonatal ALD and AMN are caused by a mutation in the same gene at Xq28. It showed, furthermore, that phenotypic differences between ALD and AMN are not necessarily the consequence of allelic heterogeneity due to different mutations within the same gene. The maximal lod score for linkage of the ALD/AMN gene and the multiallelic anonymous DNA marker at DXS52 was 3.0 at a recombination fraction of 0.00. This made a prenatal or presymptomatic diagnosis and heterozygote detection by DNA analysis with this marker reliable.
Adrenoleukodystrophy↗
Two brothers with mental retardation discordant for the fragile-X syndrome.
We describe two male sibs with mental retardation discordant for the fragile-X syndrome. In the younger sib, chromosome analysis under folate deprivation showed a fragile site at Xq27.3 in 12-46% of mitoses. In the older sib, however, repeated chromosome analyses (six different cultures with analysis of 50 mitoses each) under identical conditions could not detect any fragile-X site. Using DNA probes linked to the fragile-X gene, we found evidence that the two sibs inherited a different maternal X chromosome at Xq27.3. This excluded the presence of the fragile-X syndrome in the older sib with a probability of greater than 99%.
Adult↗