Biomedical subjects

B J Keats

Publications and source records attributed to B J Keats.

At least 19 recordsLinked to original sources

PubMed1999

Genomics and hearing impairment.

Hearing impairment is clinically and genetically heterogeneous. There are >400 disorders in which hearing impairment is a characteristic of the syndrome, and family studies demonstrate that there are at least 30 autosomal loci for nonsyndromic hearing impairment. The genes that have been identified encode diaphanous (HDIA1), alpha-tectorin (TECTA), the transcription factor POU4F3, connexin 26 (GJB2), and two unconventional myosins (MYO7A and MYO15), and four novel proteins (PDS, COCH, DFNA5, DFNB9). The same clinical phenotype in hearing-impaired individuals, even those within the same family, can result from mutations in different genes. Conversely, mutations in the same gene can result in a variety of clinical phenotypes with different modes of inheritance. For example, mutations in the gene encoding MYO7A cause Usher syndrome type IB, autosomal-recessive nonsyndromic hearing impairment (DFNB2), and autosomal-dominant nonsyndromic hearing impairment (DFNA11). Additionally, the mouse ortholog of the MYO7A gene is the shaker-1 gene. Mouse models such as shaker-1 have facilitated the identification of genes that cause hearing impairment in humans. The availability of high-resolution maps of the human and mouse genomes and new technologies for gene identification are advancing molecular understanding of hearing impairment and the complex mechanisms of the auditory system.

Animals↗

PubMed1998

The mouse deafness locus (dn) is associated with an inversion on chromosome 19.

Recombination data for the mouse deafness locus (dn) on chromosome 19 are consistent with the presence of an inversion for which one of the breakpoints is between D19Mit14 and D19Mit96, a distance of less than 226 kb. Fluorescence in situ hybridization studies using a bacterial artificial chromosome on interphase (G1) nuclei provide additional support for the presence of an inversion. The dn gene is probably the orthologue of the human DFNB7/DFNB11 gene on chromosome 9.

Animals↗

PubMed1998

Identification and mutation analysis of a cochlear-expressed, zinc finger protein gene at the DFNB7/11 and dn hearing-loss loci on human chromosome 9q and mouse chromosome 19.

The DFNB7/11 locus for autosomal recessive non-syndromic hearing loss (ARNSHL) has been mapped to an approx. 1.5 Mb interval on human chromosome 9q13-q21. We have determined the cDNA sequence and genomic structure of a novel cochlear-expressed gene, ZNF216, that maps to the DFNB7/11 interval. The mouse orthologue of this gene maps to the murine dn (deafness) locus on mouse chromosome 19. The ZNF216 gene is highly conserved between human and mouse, and contains two regions that show homology to the putative zinc linger domains of other proteins. To determine it mutations in ZNF216 might be the cause of hearing loss at the DFNB7/11 locus, we screened the coding region of this gene in DFNB7/11 families by direct sequencing. No potential disease-causing mutations were found. In addition, Northern blot analysis showed no difference in ZNF216 transcript size or abundance between dn and control mice. These data Suggest that the ZNF216 gene is unlikely to be responsible for hearing loss at the DFNB7/11 and dn loci.

Algorithms↗

PubMed1998

Assembly of a high-resolution map of the Acadian Usher syndrome region and localization of the nuclear EF-hand acidic gene.

Usher syndrome type 1C (USH1C) occurs in a small population of Acadian descendants from southwestern Louisiana. Linkage and linkage disequilibrium analyses localize USH1C to chromosome 11p between markers D11S1397 and D11S1888, an interval of less than 680 kb. Here, we refine the USH1C linkage to a region less than 400 kb, between genetic markers D11S1397 and D11S1890. Using 17 genetic markers from this interval, we have isolated a contiguous set of 60 bacterial artificial chromosomes (BACs) that span the USH1C critical region. Exon trapping of BAC clones from this region resulted in the recovery of an exon of the nuclear EF-hand acidic (NEFA) gene. However, DNA sequence analysis of the NEFA cDNA from lymphocytes of affected individuals provided no evidence of mutation, making structural mutations in the NEFA protein unlikely as the cellular cause of Acadian Usher syndrome.

Bacteriophage P1↗

PubMed1998

Low intensities and 1.3 ratio produce distortion product otoacoustic emissions which are larger in heterozygous (+/dn) than homozygous (+/+) mice.

The f2/f1 frequency ratio of 1.3 in combination with stimulus levels of L1/L2 = 50/60 and 50/50 dB SPL produced a higher level of distortion product otoacoustic emissions (DPOAE) in the heterozygous (+/dn) mice than in the homozygous (+/+) mice. These results suggest that the dn gene carriers have a unique cochlear trait which may be related to the dn gene locus and expressed via a frequency- and intensity-dependent DPOAE function.

Acoustic Stimulation↗

PubMed1997

Comparative studies of the CAG repeats in the spinocerebellar ataxia type 1 (SCA1) gene.

The CAG repeat tract at the autosomal dominant spinocerebellar ataxia type 1 (SCA1) locus was analyzed in SCA1 families and French-Acadian, African-American, Caucasian, Greenland Inuit, and Thai populations. The normal alleles had 9-37 repeats, whereas disease alleles contained 44-64 repeats. The CAG repeat tract contained one or two CAT interruptions in 44 of 47 normal human chromosomes and in all five chimpanzees examined. In contrast, no CAT interruptions were found in Old World monkeys or expanded human alleles. The number and positions of CAT interruptions may be important in stabilizing CAG repeat tracts in normal chromosomes. At least five codons occupy the region corresponding to the polyglutamine tract at the SCA1 locus in mice, rats, and other rodents. They comprise three or four CCN (coding for proline) in addition to one or two CAG repeats.

Amino Acid Sequence↗

PubMed1997

Norrie disease gene mutation in a large Costa Rican kindred with a novel phenotype including venous insufficiency.

A large Costa Rican kindred has been identified with 15 males affected with congenital blindness, progressive bearing loss, and venous insufficiency. Due to ophthalmological and audio-otological findings, including bilateral retinal dysplasia and detachment, progressive bilateral sensorineural hearing loss, and an X-linked pattern of inheritance, a tentative diagnosis of Norrie disease was considered. However, venous insufficiency is a clinical finding not reportedly associated with Norrie disease. Genetic linkage analysis using microsatellite repeat markers demonstrated linkage to Xp11.23-11.4 (z = 2.723 at theta = 0.0). A candidate gene approach using the Norrie disease gene (NDP), which maps to Xp11.3, revealed a point mutation in the third exon resulting in substitution of phenylalanine for leucine at position 61. The precise function of the gene product, norrin, has yet to be elucidated; however, it has been postulated to be involved in the regulation of neural cell differentiation and proliferation, although hypotheses have been considered for its role in vascular development in the eye. The finding of a mutation in NDP in association with peripheral vascular disease may provide valuable insight into the potential role of this gene in cellular processes.

Blindness↗

PubMed1997

Phenotypic variability in Friedreich ataxia: role of the associated GAA triplet repeat expansion.

We studied genotype-phenotype correlations in a group of 100 patients with typical Friedreich ataxia (FRDA), and in three groups of patients with atypical clinical presentations, including 44 Acadian FRDA, 8 late-onset FRDA (LOFA), and 6 FRDA with retained reflexes (FARR). All patients, except 3 with typical FRDA, carried two copies of the FRDA-associated GAA triplet repeat expansion. Overall, the phenotypic spectrum of FRDA appeared to be wider than defined by the currently used diagnostic criteria. Our study indicated the existence of several sources of variability in FRDA. Patients with larger GAA expansions tended to have earlier onset and were more likely to show additional manifestations of the disease. Mitotic instability of the expanded GAA repeats may partially account for the limited degree of correlation between expansion sizes as determined in lymphocytes and clinical parameters. Some clinical variants associated with specific FRDA haplotypes, such as Acadian FRDA and FARR, turned out to be unrelated to expansion sizes. No polymorphism in the frataxin coding sequence could be associated with these clinical variants.

Adolescent↗

PubMed1996

Phenotypic patterns of distortion product otoacoustic emission in inbred and F1 hybrid hearing mouse strains.

Distortion product otoacoustic emissions (DPOE) were obtained from five different hearing mouse groups: CBA/J, MOLF/Rk, ct (homozygous normal mice of the curly-tail stock), and the F1 hybrid offspring of the matings CBA/J x dn/dn and MOLF/Rk x dn/dn (dn/dn mice are the curly-tail stock with recessive deafness). The DPOE patterns of the CBA/J and ct strains were similar to each other and different from that of the MOLF/Rk. The two sets of F1 hybrid mice, (CBA/J x dn/dn)F1 and (MOLF/Rk x dn/dn)F1, were found to have significantly larger DPOE amplitudes than their hearing parent strains, MOLF/Rk and CBA/J, respectively. In addition, the DPOE amplitudes were greater for the offspring of the MOLF/Rk x dn/dn cross than for those of the CBA/J x dn/dn cross, even though they were lower for MOLF/Rk than for CBA/J. The distinct features of DPOE patterns among these five groups suggest that DPOE testing can be used for auditory phenotyping.

Animals↗

PubMed1996

Linkage map integration.

The algorithms that drive the map+ program for locus-oriented linkage mapping are presented. They depend on the enhanced location database program ldb+ to specify an initial comprehensive map that includes all loci in the summary lod file. Subsequently the map may be edited or order constrained and is automatically improved by estimating the location of each locus conditional on the remainder, beginning with the most discrepant loci. Operating characteristics permit rapid and accurate construction of linkage maps with several hundred loci. The map+ program also performs nondisjunction mapping with tests of nonstandard recombination. We have released map+ on Internet as a source program in the C language together with the location database that now includes the LODSOURCE database. The anonymous ftp is cedar.genetics.soton.ac.uk and the World Wide Web address is http://cedar.genetics.soton.ac.uk/public_html.

Algorithms↗

PubMed1996

Genetic variation of recent Alu insertions in human populations.

The Alu family of interspersed repeats is comprised of over 500,000 members which may be divided into discrete subfamilies based upon mutations held in common between members. Distinct subfamilies of Alu sequences have amplified within the human genome in recent evolutionary history. Several individual Alu family members have amplified so recently in human evolution that they are variable as to presence and absence at specific loci within different human populations. Here, we report on the distribution of six polymorphic Alu insertions in a survey of 563 individuals from 14 human population groups across several continents. Our results indicate that these polymorphic Alu insertions probably have an African origin and that there is a much smaller amount of genetic variation between European populations than that found between other population groups.

Base Sequence↗

PubMed1996

Analysis of CAG repeat of the Machado-Joseph gene in human, chimpanzee and monkey populations: a variant nucleotide is associated with the number of CAG repeats.

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder associated with an unstable and expanded CAG repeat. We analyzed this locus from various sources including MJD families, Acadian, African American, Caucasian, Greenland Inuit and Thai populations. The range of the CAG repeat size was 14-40 in the normal alleles while the MJD alleles contained 73-78 repeats in our studies. We found 25 different alleles on normal chromosomes with a heterozygosity of 0.86 in combined populations. The most common alleles were 23 (22.9%) and 14 (25.5%) repeats. We also examined 16 chimpanzees and various Old World monkeys: a pigtail macaque, a mangabey and 12 rhesus macaques. The DNA sequences surrounding the CAG repeat did not vary among species. The range of the number of the CAG repeats is 13-14 in macaques, 16 in mangabey and 14-20 in chimpanzees. Variant CAA or AAG triplets in the CAG repeat tracts were found in all 268 human, 28 monkey and 32 chimpanzee chromosomes. As reported in a previous study [Kawaguchi et al. (1994) Nature Genet. 8, 221-228] the common variant positions were the third (CAA), fourth (AAG) and sixth (CAA) positions. However, we found three human chromosomes containing CAG at the sixth position and the mangabey had AAG at the ninth position. In addition, we found CAG at the fourth position and AAG at the sixth position in all macaque chromosomes. The nucleotide following the CAG repeat tract was usually G in all species studied. However, we sometimes found C at this position in human and chimpanzee chromosomes. Interestingly, this variant C was found in all expanded chromosomes and in 54.5% of chromosomes with 27-40 CAG repeats but it was not found in any chromosomes with less than 20 CAG repeats. We hypothesize that the variant C may be associated with CAG repeat instability.

Animals↗

PubMed1995

A locus for axonal motor-sensory neuropathy with deafness and mental retardation maps to Xq24-q26.

DNA markers on the X chromosome were used to map the locus for an unusual form of X-linked recessive hereditary motor and sensory neuropathy with associated deafness and mental retardation in a three-generation family that was originally reported by Cowchock et al. (Am, J. Hum. Genet. 35: 85A, 1993; Am. J. Med. Genet. 20: 307-315, 1985). This family included seven affected males, three obligate carrier females, and four unaffected males. The patients were severely affected within the first few years of life with distal weakness, muscle atrophy, sensory loss, areflexia, pes cavus, and hammer toes. Five of the seven affected males showed associated deafness, and three of these five individuals also presented with mental retardation or social developmental delay. Motor nerve conduction velocities in affected males were normal to mildly delayed, and sensory conduction was markedly abnormal. Heterozygous females were asymptomatic. Close linkage to the Xg blood group locus (Xp22) and the PGK locus (Xq13) was previously excluded in this family, while weak linkage of the disease gene to DXYS1 (XQ21.3) was suggested. Our current linkage studies and haplotype analysis of 19 microsatellite markers on the long arm of the X chromosome demonstrate that DXS425 (Xq24) and HPRT (Xq26.1) are flanking markers and that the disease gene is closely linked to the markers DXS1122, DXS994, DXS737, DXS1206, and DXS1047.

Chromosome Mapping↗

PubMed1995

The deafness locus (dn) maps to mouse chromosome 19.

The deafness mouse has profound sensorineural hearing loss with degeneration of hair cells soon after birth. The mode of inheritance is recessive, and there are no associated phenotypic anomalies. Thus, this mouse provides a model for recessive, non-syndromic, prelingual deafness. We have mapped the gene causing deafness in the mouse to Chromosome (Chr) 19 by analysis of 230 intersubspecific backcross progeny. No recombinants were found with the microsatellite marker D19Mit14. The loci for two guanine nucleotide-binding proteins are tightly linked to this marker, and they are being investigated as possible candidate genes. The identification of the defective gene in the mouse will help to explain the mechanism that causes hair cell degeneration and is likely to identify a homologous gene for deafness in humans.

Animals↗

PubMed1995

Auditory phenotyping of heterozygous sound-responsive (+/dn) and deafness (dn/dn) mice.

Accurate phenotyping of offspring from backcross matings between F1 heterozygous sound-responsive and deafness mice is an important step for the identification of the deafness (dn) gene (Keats et al., 1995). Here, we report the results of auditory phenotyping of backcross offspring who are either sound-responsive or deaf by recording the Preyer reflex elicited by hand clap, auditory brainstem responses (ABRs), and 2f1-f2 distortion product otoacoustic emissions (DPOEs). Our results show that the Preyer reflex observation alone is inadequate for auditory phenotyping; a more precise test such as a click-evoked ABR recording is needed for auditory phenotyping. DPOE recording results in identification of sound-responsive or deaf mice as accurately as the click-evoked ABR testing. In addition, because the DPOE amplitude function is in good agreement with the ABR threshold in frequency sensitivity and specificity for stimulus frequencies between 1 and 16 kHz, the DPOE recording can be considered as an alternate test for auditory phenotyping.

Acoustic Stimulation↗

PubMed1994

Clinical diagnosis of the Usher syndromes. Usher Syndrome Consortium.

The Usher syndromes are genetically distinct disorders which share specific phenotypic characteristics. This paper describes a set of clinical criteria recommended for the diagnosis of Usher syndrome type I and Usher syndrome type II. These criteria have been adopted by the Usher Syndrome Consortium and are used in studies reported by members of this Consortium.

Diagnosis, Differential↗

PubMed1994

Integration of gene maps: chromosome X.

Omitting 1137 loci that are included in the location database but have only cytogenetic assignment, there are 605 loci in the integrated map that synthesizes physical and genetic data and subsumes a composite physical location, cytogenetic and regional assignments, mouse homology, rank, and references. With error filtration and allowance for interference the genetic length is 211 cM, to which the p arm contributes 100 cM. The physical length is 164 Mb, with 62 Mb in the p arm. Current problems in map integration are discussed and some solutions proposed.

Animals↗

PubMed1994

A gene for Crouzon craniofacial dysostosis maps to the long arm of chromosome 10.

Crouzon craniofacial dysostosis (CFD) is an autosomal dominant craniofacial disorder characterized by premature craniosynostosis, shallow orbits and hypoplastic maxilla. To map the gene responsible, we have used a mapping strategy of testing for linkage to known developmental genes. Analysis of a large kindred established linkage between CFD and three loci (D10S190, D10S209 and D10S216) that span a 13 cM region on chromosome 10q. A maximum pairwise lod score of 4.42 (theta = 0) at D10S190 was obtained and the addition of a second kindred produced a combined pairwise lod score of 5.32 (theta = 0) at the same locus. The developmental gene, PAX2, located within this region, is an attractive candidate gene.

Chromosome Mapping↗