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Biomedical subjects

W J Kimberling

Publications and source records attributed to W J Kimberling.

At least 19 recordsLinked to original sources
PubMed2002

CDH23 mutation and phenotype heterogeneity: a profile of 107 diverse families with Usher syndrome and nonsyndromic deafness.

Usher syndrome type I is characterized by congenital hearing loss, retinitis pigmentosa (RP), and variable vestibular areflexia. Usher syndrome type ID, one of seven Usher syndrome type I genetic localizations, have been mapped to a chromosomal interval that overlaps with a nonsyndromic-deafness localization, DFNB12. Mutations in CDH23, a gene that encodes a putative cell-adhesion protein with multiple cadherin-like domains, are responsible for both Usher syndrome and DFNB12 nonsyndromic deafness. Specific CDH23 mutational defects have been identified that differentiate these two phenotypes. Only missense mutations of CDH23 have been observed in families with nonsyndromic deafness, whereas nonsense, frameshift, splice-site, and missense mutations have been identified in families with Usher syndrome. In the present study, a panel of 69 probands with Usher syndrome and 38 probands with recessive nonsyndromic deafness were screened for the presence of mutations in the entire coding region of CDH23, by heteroduplex, single-strand conformation polymorphism, and direct sequence analyses. A total of 36 different CDH23 mutations were detected in 45 families; 33 of these mutations were novel, including 18 missense, 3 nonsense, 5 splicing defects, 5 microdeletions, and 2 insertions. A total of seven mutations were common to more than one family. Numerous exonic and intronic polymorphisms also were detected. Results of ophthalmologic examinations of the patients with nonsyndromic deafness have found asymptomatic RP-like manifestations, indicating that missense mutations may have a subtle effect in the retina. Furthermore, patients with mutations in CDH23 display a wide range of hearing loss and RP phenotypes, differing in severity, age at onset, type, and the presence or absence of vestibular areflexia.

Adolescent↗
PubMed2001

Connexin 26 gene (GJB2) mutation modulates the severity of hearing loss associated with the 1555A-->G mitochondrial mutation.

We report a high prevalence of GJB2 heterozygous mutations in patients bearing the 1555A-->G mitochondrial mutation, and describe a family in which potential interaction between GJB2 and a mitochondrial gene appears to be the cause of hearing impairment. Patients who are heterozygotes for the GJB2 mutant allele show hearing loss more severe than that seen in sibs lacking a mutant GJB2 allele, suggesting that heterozygous GJB2 mutations may synergistically cause hearing loss when in the presence of a 1555A-->G mutation. The present findings indicate that GJB2 mutations may sometimes be an aggravating factor, in addition to aminoglycoside antibiotics, in the phenotypic expression of the non-syndromic hearing loss associated with the 1555A-->G mitochondrial mutation.

Connexin 26↗
PubMed2001

A common ancestral origin of the frequent and widespread 2299delG USH2A mutation.

Usher syndrome type IIa is an autosomal recessive disorder characterized by mild-to-severe hearing loss and progressive visual loss due to retinitis pigmentosa. The mutation that most commonly causes Usher syndrome type IIa is a 1-bp deletion, described as "2299delG," in the USH2A gene. The mutation has been identified in several patients from northern and southern Europe and from North America, and it has been found in single patients from South America, South Africa, and China. Various studies have reported a range of frequencies (.16-.44) among patients with Usher syndrome, depending on the geographic origin of the patients. The 2299delG mutation may be the one that most frequently causes retinitis pigmentosa in humans. Given the high frequencies and the wide geographic distribution of the mutation, it was of interest to determine whether the mutation resulted from an ancestral mutational event or represented a mutational hotspot in the USH2A gene. Haplotype analysis was performed on DNA samples from 116 unrelated patients with Usher syndrome type IIa; the patients were from 14 countries and represented 148 2299delG alleles. On the basis of six single-nucleotide polymorphisms within the USH2A gene, 12 core haplotypes were observed in a panel of normal chromosomes. However, in our analysis, only one core haplotype was found to be associated with the 2299delG mutation. The data indicate that the widespread geographic distribution of the 2299delG mutation is the result of an ancestral mutation that has spread throughout Europe and into the New World as a result of migration.

Alleles↗
PubMed2001

Spectrum of mutations in USH2A in British patients with Usher syndrome type II.

Usher syndrome (USH) is a combination of a progressive pigmentary retinopathy, indistinguishable from retinitis pigmentosa, and some degree of sensorineural hearing loss. USH can be subdivided in Usher type I (USHI), type II (USHII) and type III (USHIII), all of which are inherited as autosomal recessive traits. The three subtypes are genetically heterogeneous, with six loci so far identified for USHI, three for USHII and only one for USHIII. Mutations in a novel gene, USH2A, encoding the protein usherin, have recently been shown to be associated with USHII. The gene encodes a protein with partial sequence homology to both laminin epidermal growth factor and fibronectin motifs. We analysed 35 British and one Pakistani Usher type II families with at least one affected member, for sequence changes in the 20 translated exons of the USH2A gene, using heteroduplex analysis and sequencing. Probable disease-causing mutations in USH2A were identified in 15 of 36 (41.7%) Usher II families. The most frequently encountered mutation (11/15 families or 11/18 mutated alleles) was del2299G in exon 13, resulting in a frameshift and premature stop codon. Other mutations include insertions and point mutations, of which two are previously unreported. Five different polymorphisms were also detected. Our results indicate that mutations in this gene are responsible for disease in a large proportion of British Usher type II patients. Moreover, if screening for mutations in USH2A is considered, it is sensible to screen for the del2299G mutation first.

Chromosome Deletion↗
PubMed2001

Genetic features of hearing loss associated with ear anomalies: PDS and EYA1 mutation analysis.

Mutation analysis of the PDS gene and the EYA1 gene, which are reported to be responsible for hearing loss associated with ear anomalies, was performed in 24 deaf patients with various middle and inner ear anomalies. The present study was done to clarify the spectrum of middle and inner ear malformations covered by these two genes. PDS mutations were found only in patients with enlarged vestibular aqueducts and EYA1 mutations were detected only in patients with ear pits and cervical fistulae, indicating that these two genes are associated with particular forms of middle and inner ear malformation. The genetic approach provides a strong tool for the diagnosis of hearing loss associated with ear anomalies.

Adolescent↗
PubMed2001

Clinical and genetic features of nonsyndromic autosomal dominant sensorineural hearing loss: KCNQ4 is a gene responsible in Japanese.

Sixteen Japanese nonsyndromic autosomal dominant sensorineural hearing loss (ADSNHL) families were investigated clinically as well as genetically. Most families showed postlingual hearing loss. Although the severity of their hearing loss varied, most patients showed mild-moderate sensorineural hearing loss of a progressive nature. Mutation analysis was performed for the MYO7A, KCNQ4, and GJB3 genes, which are known to be responsible for autosomal dominant sensorineural hearing loss. The present study reports that a mutation in KCNQ4, a member of a large family of potassium channel genes, was responsible for ADSNHL in one Japanese family.

Adolescent↗
PubMed2001

A new clinical classification for Usher's syndrome based on a new subtype of Usher's syndrome type I.

OBJECTIVES: Usher's syndrome is an autosomal recessive disorder characterized by sensorineural hearing loss and progressive visual loss secondary to retinitis pigmentosa. Usher's syndrome is both clinically and genetically heterogeneous. Three clinical types are known today. METHODS: We conducted a study on 74 patients with Usher's syndrome, performing complete audiological and neurotological examinations. RESULTS: Twenty-six patients had total profound hearing loss and retinitis pigmentosa (Usher's syndrome type I), and 48 patients had moderate to severe sensorineural hearing loss and retinitis pigmentosa (Usher's syndrome type II). We identified 9 of the 26 Usher's syndrome patients with profound hearing loss who showed a normal response to bithermal vestibular testing. CONCLUSIONS: The combination of profound hearing loss and normal response to bithermal vestibular testing has not been previously described in Usher's syndrome. Therefore we describe a new subtype of Usher's syndrome type I and suggest a modified clinical classification for Usher's syndrome.

Adult↗
PubMed2000

Genetic heterogeneity of Usher syndrome: analysis of 151 families with Usher type I.

Usher syndrome type I is an autosomal recessive disorder marked by hearing loss, vestibular areflexia, and retinitis pigmentosa. Six Usher I genetic subtypes at loci USH1A-USH1F have been reported. The MYO7A gene is responsible for USH1B, the most common subtype. In our analysis, 151 families with Usher I were screened by linkage and mutation analysis. MYO7A mutations were identified in 64 families with Usher I. Of the remaining 87 families, who were negative for MYO7A mutations, 54 were informative for linkage analysis and were screened with the remaining USH1 loci markers. Results of linkage and heterogeneity analyses showed no evidence of Usher types Ia or Ie. However, one maximum LOD score was observed lying within the USH1D region. Two lesser peak LOD scores were observed outside and between the putative regions for USH1D and USH1F, on chromosome 10. A HOMOG chi(2)((1)) plot shows evidence of heterogeneity across the USH1D, USH1F, and intervening regions. These results provide conclusive evidence that the second-most-common subtype of Usher I is due to genes on chromosome 10, and they confirm the existence of one Usher I gene in the previously defined USH1D region, as well as providing evidence for a second, and possibly a third, gene in the 10p/q region.

Abnormalities, Multiple↗
PubMed2000

Genomewide search and genetic localization of a second gene associated with autosomal dominant branchio-oto-renal syndrome: clinical and genetic implications.

Branchio-oto-renal (BOR) syndrome is characterized by ear malformations, cervical fistulas, hearing loss, and renal anomalies. It is an autosomal dominant disorder with variable clinical manifestations. The most common features of BOR syndrome are branchial, hearing, and renal anomalies. However, many affected subjects have been observed with branchial-cleft anomalies and hearing loss but without renal anomalies, a condition called "branchio-otic" (BO) syndrome. It is logical to question whether the BOR and BO syndromes are allelic or whether they represent distinct genetic entities. We identified a very large extended family whose members had branchial and hearing anomalies associated with commissural lip pits that segregated in an autosomal dominant fashion. Using a genomewide search strategy, we identified genetic linkage, with a maximum LOD score of 4.81 at recombination fraction 0, between the BO phenotype and polymorphic marker D1S2757 in the genetic region of chromosome 1q31. This is the first report of linkage for a second gene associated with BOR syndrome. The findings have important clinical implications and will provide insight into the genetic basis of BOR syndrome.

Alleles↗
PubMed2000

Genomic structure and identification of novel mutations in usherin, the gene responsible for Usher syndrome type IIa.

Usher syndrome type IIa (USHIIa) is an autosomal recessive disorder characterized by moderate to severe sensorineural hearing loss and progressive retinitis pigmentosa. This disorder maps to human chromosome 1q41. Recently, mutations in USHIIa patients were identified in a novel gene isolated from this chromosomal region. The USH2A gene encodes a protein with a predicted molecular weight of 171.5 kD and possesses laminin epidermal growth factor as well as fibronectin type III domains. These domains are observed in other protein components of the basal lamina and extracellular matrixes; they may also be observed in cell-adhesion molecules. The intron/exon organization of the gene whose protein we name "Usherin" was determined by direct sequencing of PCR products and cloned genomic DNA with cDNA-specific primers. The gene is encoded by 21 exons and spans a minimum of 105 kb. A mutation search of 57 independent USHIIa probands was performed with a combination of direct sequencing and heteroduplex analysis of PCR-amplified exons. Fifteen new mutations were found. Of 114 independent USH2A alleles, 58 harbored probable pathologic mutations. Ten cases of USHIIa were true homozygotes and 10 were compound heterozygotes; 18 heterozygotes with only one identifiable mutation were observed. Sixty-five percent (38/58) of cases had at least one mutation, and 51% (58/114) of the total number of possible mutations were identified. The allele 2299delG (previously reported as 2314delG) was the most frequent mutant allele observed (16%; 31/192). Three new missense mutations (C319Y, N346H, and C419F) were discovered; all were restricted to the previously unreported laminin domain VI region of Usherin. The possible significance of this domain, known to be necessary for laminin network assembly, is discussed in the context of domain VI mutations from other proteins.

Amino Acid Sequence↗
PubMed2000

Erratum: analysis of DNA elements that modulate myosin VIIa expression in humans.

Usher syndromeIb (USH1B), an autosomal recessive disorder caused by mutations in myosin VIIa (MYO7A), is characterized by congenital profound hearing loss, vestibular abnormalities and retinitis pigmentosa. Promoter elements in the 5 kb upstream of the translation start were identified using adult retinal pigment epithelium cells (ARPE-19) as a model system. A 160 bp minimal promoter within the first intron was active in ARPE-19 cells, but not in HeLa cells that do not express MYO7A. A 100 bp sequence, 5' of the first exon, and repeated with 90% homology within the first intron, appeared to modulate expression in both cell lines. Segments containing these elements were screened by heteroduplex analysis. No heteroduplexes were detected in the minimal promoter, suggesting that this sequence is conserved. A -2568 A>T transversion in the 5' 100 bp repeat, eliminating a CCAAT element, was found only in USH1B patients. However, in all 5 families, -2568 A>T was in cis with the same missense mutation in the myosin VIIa tail (Arg1240Gln), and 4 of the 5 families were Dutch. These observations suggest either 1) linkage disequilibrium or 2)that a combination of a promoter mutation with a less active myosin VIIa protein results in USH1B.

Amino Acid Substitution↗
PubMed2000

Three novel mutations and twelve polymorphisms identified in the USH2A gene in Israeli USH2 families.

The Usher syndromes are autosomal recessive hereditary disorders characterized by hearing impairment and progressive visual loss due to Retinitis Pigmentosa (RP). Moderate to severe sensorineural hearing loss and progressive RP characterizes Usher syndrome type IIa (USH2A), which maps to the long arm of chromosome 1q41. Recently, three deletions carried by USH2 patients, which were found in a novel gene isolated from the critical 1q41 region, defined this gene as responsible for USH2A. The USH2A gene is predicted to encode a 1546 amino acid protein which possesses domains that are observed in basal lamina and extracellular matrix proteins and in cell adhesion molecules. Affected individuals and additional members from eleven USH2 Israeli families of diverse ethnic origin were screened for the presence of changes in all 20 coding exons of the USH2A gene. Three novel mutations (239-242insCGTA, R334W, T1515M) were identified in three families of Jewish Moroccan and Jewish Iranian origins. Twelve polymorphisms were found in the families, four of which are novel. None of the known USH2 mutations were identified in the families studied in this work. Hum Mutat 15:388, 2000.

Adolescent↗
PubMed2000

Connexin 26: required for normal auditory function.

A single base deletion mutation, 35delG, in the gene (GJB2/DFNB1)(OMIM 121011/220290) encoding the gap junction protein, connexin 26 is the most important single cause of genetic hearing loss in European and American populations. It is the cause of one of the most common human genetic disorders with a frequency similar to cystic fibrosis. Mutations in this connexin are associated with skin disorders.

Connexin 26↗
PubMed2000

Identification of novel USH2A mutations: implications for the structure of USH2A protein.

Usher syndrome type II is an autosomal recessive disorder, characterised by stable hearing impairment from childhood and progressive retinitis pigmentosa from the late teens. Mutations in the USH2A gene, located on 1q41, were recently shown to be responsible for Usher syndrome type IIa. We have investigated the molecular pathology of Usher type II by screening the USH2A gene for mutations in 31 unrelated patients from Denmark and Norway. Besides the frequent 2299delG mutation, which accounted for 44% of the disease alleles, a heterogeneous spectrum of mutations was identified. Sixteen new, putative disease-causing mutations were detected, of which 12 were private and four were shared by unrelated patients. The disease-causing mutations were scattered throughout the gene and included six nonsense and seven missense mutations, two deletions and one small insertion. In addition, six non-pathogenic polymorphisms were identified. All missense mutations resulted in major amino acid side-chain alterations. Four missense mutations affected the N-terminal part of USH2A, whereas three missense mutations affected the laminin-type epidermal growth factor-like (LE) domain. The structural consequences of the mutations affecting the LE domain are discussed in relation to the three-dimensional structure of a LE-module of the mouse laminin gamma1 chain.

Adolescent↗
PubMed2000

Prevalent connexin 26 gene (GJB2) mutations in Japanese.

The gene responsible for DNFB1 and DFNA3, connexin 26 (GJB2), was recently identified and more than 20 disease causing mutations have been reported so far. This paper presents mutation analysis for GJB2 in Japanese non-syndromic hearing loss patients compatible with recessive inheritance. It was confirmed that GJB2 mutations are an important cause of hearing loss in this population, with three mutations, 235delC, Y136X, and R143W, especially frequent. Of these three mutations, 235delC was most prevalent at 73%. Surprisingly, the 35delG mutation, which is the most common GJB2 mutation in white subjects, was not found in the present study. Our data indicated that specific combinations of GJB2 mutation exist in different populations.

Amino Acid Substitution↗
PubMed2000

Genetic heterogeneity of Usher syndrome type II: localisation to chromosome 5q.

Usher syndrome is a group of autosomal recessive disorders that includes retinitis pigmentosa (RP) with hearing loss. Usher syndrome type II is defined as moderate to severe hearing loss with RP. The USH2A gene at 1q41 has been isolated and characterised. In 1993, a large Usher II family affected with a mild form of RP was found to be unlinked to 1q41 markers. Subsequent linkage studies of families in our Usher series identified several type II families unlinked to USH2A and USH3 on 3q25. After a second unlinked family with many affected members and a mild retinal phenotype was discovered, a genome search using these two large families showed another Usher II locus on 5q (two point lod = 3.1 at D5S484). To date, we have identified nine unrelated 5q linked families (maximum combined multipoint lod = 5.86) as well as three Usher II families that show no significant linkage to any known Usher loci. Haplotype analysis of 5q markers indicates that the new locus is flanked by D5S428 and D5S433. Review of ophthalmological data suggests that RP symptoms are milder in 5q linked families; the RP is often not diagnosed until patients near their third decade. Enamel hypoplasia and severe, very early onset RP were observed in two of the three unlinked families; dental anomalies have not been previously described as a feature of Usher type II.

Chromosome Mapping↗
PubMed2000

Genetic heterogeneity of Usher syndrome.

Progress towards the understanding of the molecular basis of US has been substantial. Nine different loci have been found to be responsible and two have had the specific gene identified. This information is expected to lay the foundation for the eventual development of new treatment strategies. Usher syndrome is the combined loss of both of humans most important two senses and a better understanding of the genes involved should not only help the families with US but will also provide much needed basic information about the hearing and visual systems.

Chromosome Mapping↗