PubMed Health⌕ Search

Biomedical subjects

A J Griffith

Publications and source records attributed to A J Griffith.

At least 19 recordsLinked to original sources
PubMed2005

Genetic basis of hearing loss associated with enlarged vestibular aqueducts in Koreans.

Sensorineural hearing loss associated with enlargement of the vestibular aqueduct (EVA) can be associated with mutations of the SLC26A4 gene. In western populations, less than one-half of the affected individuals with EVA have two mutant SLC26A4 alleles, and EVA is frequently caused by unknown genetic or environmental factors alone or in combination with a single SLC26A4 mutation as part of a complex trait. In this study, we ascertained 26 Korean probands with EVA and performed nucleotide sequence analysis to detect SLC26A4 mutations. All subjects had bilateral EVA, and 20 of 26 were sporadic (simplex) cases. Fourteen different mutations were identified, including nine novel mutations. Five mutations were recurrent and accounted for 80% of all mutant alleles, providing a basis for the design and interpretation of cost-efficient mutation detection algorithms. Two mutant alleles were identified in 21 (81%), one mutant allele was detected in three (11%), and zero mutant allele was detected in two (8%) of 26 probands. The high proportion of Korean probands with two SLC26A4 mutations may reflect a reduced frequency of other genetic or environmental factors causing EVA in comparison to western populations.

Adolescent↗
PubMed2004

Mutations of ESPN cause autosomal recessive deafness and vestibular dysfunction.

We mapped a human deafness locus DFNB36 to chromosome 1p36.3 in two consanguineous families segregating recessively inherited deafness and vestibular areflexia. This phenotype co-segregates with either of two frameshift mutations, 1988delAGAG and 2469delGTCA, in ESPN, which encodes a calcium-insensitive actin-bundling protein called espin. A recessive mutation of ESPN is known to cause hearing loss and vestibular dysfunction in the jerker mouse. Our results establish espin as an essential protein for hearing and vestibular function in humans. The abnormal vestibular phenotype associated with ESPN mutations will be a useful clinical marker for refining the differential diagnosis of non-syndromic deafness.

Adolescent↗
PubMed2003

Origins and frequencies of SLC26A4 (PDS) mutations in east and south Asians: global implications for the epidemiology of deafness.

Recessive mutations of SLC26A4 (PDS) are a common cause of Pendred syndrome and non-syndromic deafness in western populations. Although south and east Asia contain nearly one half of the global population, the origins and frequencies of SLC26A4 mutations in these regions are unknown. We PCR amplified and sequenced seven exons of SLC26A4 to detect selected mutations in 274 deaf probands from Korea, China, and Mongolia. A total of nine different mutations of SLC26A4 were detected among 15 (5.5%) of the 274 probands. Five mutations were novel and the other four had seldom, if ever, been identified outside east Asia. To identify mutations in south Asians, 212 Pakistani and 106 Indian families with three or more affected offspring of consanguineous matings were analysed for cosegregation of recessive deafness with short tandem repeat markers linked to SLC26A4. All 21 SLC26A4 exons were PCR amplified and sequenced in families segregating SLC26A4 linked deafness. Eleven mutant alleles of SLC26A4 were identified among 17 (5.4%) of the 318 families, and all 11 alleles were novel. SLC26A4 linked haplotypes on chromosomes with recurrent mutations were consistent with founder effects. Our observation of a diverse allelic series unique to each ethnic group indicates that mutational events at SLC26A4 are common and account for approximately 5% of recessive deafness in south Asians and other populations.

Asia, Southeastern↗
PubMed2001

Mutations of the protocadherin gene PCDH15 cause Usher syndrome type 1F.

Human chromosome 10q21-22 harbors USH1F in a region of conserved synteny to mouse chromosome 10. This region of mouse chromosome 10 contains Pcdh15, encoding a protocadherin gene that is mutated in ames waltzer and causes deafness and vestibular dysfunction. Here we report two mutations of protocadherin 15 (PCDH15) found in two families segregating Usher syndrome type 1F. A Northern blot probed with the PCDH15 cytoplasmic domain showed expression in the retina, consistent with its pathogenetic role in the retinitis pigmentosa associated with USH1F.

Aged↗
PubMed2001

Mutations in the gene encoding tight junction claudin-14 cause autosomal recessive deafness DFNB29.

Tight junctions in the cochlear duct are thought to compartmentalize endolymph and provide structural support for the auditory neuroepithelium. The claudin family of genes is known to express protein components of tight junctions in other tissues. The essential function of one of these claudins in the inner ear was established by identifying mutations in CLDN14 that cause nonsyndromic recessive deafness DFNB29 in two large consanguineous Pakistani families. In situ hybridization and immunofluorescence studies demonstrated mouse claudin-14 expression in the sensory epithelium of the organ of Corti.

Blotting, Northern↗
PubMed2001

Auditory dysfunction in Stickler syndrome.

OBJECTIVES: To characterize the natural history and possible mechanisms of hearing loss in Stickler syndrome (OMIM 108300; or hereditary progressive arthro-ophthalmopathy) and to determine if the auditory phenotype is a useful discriminating feature for the differential diagnosis of this group of disorders. DESIGN: Multifamily study. SETTING: Outpatient audiology and otolaryngology clinics at the Warren Grant Magnuson Clinical Center of the National Institutes of Health, Rockville, Md. SUBJECTS: Forty-six affected individuals from 29 different families segregating Stickler syndrome. INTERVENTIONS: Clinical audiologic and otolaryngological examinations were performed on all individuals, including pure-tone audiometry, speech audiometry, and middle ear immittance testing. Otoacoustic emissions, auditory brainstem response, infrared video electronystagmography, and temporal bone computed tomography were performed on a subset of participants. RESULTS: The hearing loss was most often sensorineural in adults, and approximately 28 (60%) of the 46 adult patients had 2 or more thresholds greater than the corresponding 95th percentile values for an age-matched, otologically normal population. The hearing loss most often affected high frequencies (4000-8000 Hz) and was generally no more progressive than that due to age-related hearing loss. Type A(D) tympanograms (classification using the Jerger model), indicating hypermobile middle ear systems, were observed in 21 (46%) of the 46 affected individuals. Computed tomography of the temporal bones revealed no inner ear malformations in 19 affected individuals. CONCLUSIONS: The hypermobile middle ear systems observed in ears with normal-appearing tympanic membranes represent a novel finding for Stickler syndrome and are likely to be a useful diagnostic feature for this disorder. The overall sensorineural hearing loss in type I Stickler syndrome is typically mild and not significantly progressive. It is less severe than that reported for types II and III Stickler syndrome linked to COL11A2 (OMIM 120290) and COL11A1 (OMIM 120280) mutations, respectively, or the closely related Marshall syndrome. This difference will be a useful discriminatory feature in the differential diagnosis of this group of disorders.

Adolescent↗
PubMed2000

Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23.

Genes causing nonsyndromic autosomal recessive deafness (DFNB12) and deafness associated with retinitis pigmentosa and vestibular dysfunction (USH1D) were previously mapped to overlapping regions of chromosome 10q21-q22. Seven highly consanguineous families segregating nonsyndromic autosomal recessive deafness were analyzed to refine the DFNB12 locus. In a single family, a critical region was defined between D10S1694 and D10S1737, approximately 0.55 cM apart. Eighteen candidate genes in the region were sequenced. Mutations in a novel cadherin-like gene, CDH23, were found both in families with DFNB12 and in families with USH1D. Six missense mutations were found in five families with DFNB12, and two nonsense and two frameshift mutations were found in four families with USH1D. A northern blot analysis of CDH23 showed a 9.5-kb transcript expressed primarily in the retina. CDH23 is also expressed in the cochlea, as is demonstrated by polymerase chain reaction amplification from cochlear cDNA.

Alleles↗
PubMed2000

Autosomal recessive nonsyndromic neurosensory deafness at DFNB1 not associated with the compound-heterozygous GJB2 (connexin 26) genotype M34T/167delT.

Previous studies of the gap-junction beta-2 subunit gene GJB2 (connexin 26) have suggested that the 101T-->C (M34T) nucleotide substitution may be a mutant allele responsible for recessive deafness DFNB1. This hypothesis was consistent with observations of negligible intercellular coupling and gap-junction assembly of the M34T allele product expressed in Xenopus oocytes and HeLa cells. The results of our current study of a family cosegregating the 167delT allele of GJB2 and severe DFNB1 deafness demonstrate that this phenotype did not cosegregate with the compound-heterozygous genotype M34T/167delT. Since 167delT is a null allele of GJB2, this result indicates that the in vivo activity of a single M34T allele is not sufficiently reduced to cause the typical deafness phenotype associated with DFNB1. This observation raises the possibility that other GJB2 missense substitutions may not be recessive mutations that cause severe deafness and emphasizes the importance of observing cosegregation with deafness in large families to confirm that these missense alleles are mutant DFNB1 alleles.

Alleles↗
PubMed2000

Audiovestibular phenotype associated with a COL11A1 mutation in Marshall syndrome.

BACKGROUND: Marshall syndrome is a dominant disorder characterized by craniofacial and skeletal abnormalities, sensorineural hearing loss, myopia, and cataracts, and is associated with splicing mutations in COL11A1. OBJECTIVE: To determine the auditory and vestibular phenotypes associated with a COL11A1 splicing. DESIGN: Clinical otolaryngologic, audiologic, vestibular, and radiologic evaluations of the auditory and vestibular systems. SUBJECTS: Three affected individuals from a family cosegregating Marshall syndrome and a COL11A1 splice site mutation. RESULTS: The study subjects have progressive sensorineural hearing loss that is predominantly cochlear in origin and asymptomatic dysfunction of the central and peripheral vestibular systems. Computed tomography detected no malformations of temporal bone structures. CONCLUSIONS: The observed auditory and vestibular abnormalities are not caused by defective morphogenesis of the osseous labyrinth, but by more direct effects of the COL11A1 mutation on the membranous labyrinth and the central nervous system. The onset and degree of hearing loss associated with COL11A1 mutations are useful clinical features to differentiate Marshall syndrome from the phenotypically similar Stickler syndrome.

Audiometry, Pure-Tone↗
PubMed2000

Dominant modifier DFNM1 suppresses recessive deafness DFNB26.

More than 50% of severe childhood deafness is genetically determined, approximately 70% of which occurs without other abnormalities and is thus termed nonsyndromic. So far, 30 nonsyndromic recessive deafness loci have been mapped and the defective genes at 6 loci, DFNB1, DFNB2, DFNB3, DFNB4, DFNB9 and DNFB21, have been identified, encoding connexin-26 (ref. 3), myosin VIIA (ref. 4), myosin XV (ref. 5), pendrin, otoferlin and alpha-tectorin, respectively. Here we map a new recessive nonsyndromic deafness locus, DFNB26, to a 1.5-cM interval of chromosome 4q31 in a consanguineous Pakistani family. A maximum lod score of 8.10 at theta=0 was obtained with D4S1610 when only the 8 affected individuals in this family were included in the calculation. There are seven unaffected family members who are also homozygous for the DFNB26-linked haplotype and thus are non-penetrant. A dominant modifier, DFNM1, that suppresses deafness in the 7 nonpenetrant individuals was mapped to a 5.6-cM region on chromosome 1q24 with a lod score of 4.31 at theta=0 for D1S2815.

Chromosome Mapping↗
PubMed1999

Mutations in COL11A2 cause non-syndromic hearing loss (DFNA13).

We report that mutation of COL11A2 causes deafness previously mapped to the DFNA13 locus on chromosome 6p. We found two families (one American and one Dutch) with autosomal dominant, non-syndromic hearing loss to have mutations in COL11A2 that are predicted to affect the triple-helix domain of the collagen protein. In both families, deafness is non-progressive and predominantly affects middle frequencies. Mice with a targeted disruption of Col11a2 also were shown to have hearing loss. Electron microscopy of the tectorial membrane of these mice revealed loss of organization of the collagen fibrils. Our findings revealed a unique ultrastructural malformation of inner-ear architecture associated with non-syndromic hearing loss, and suggest that tectorial membrane abnormalities may be one aetiology of sensorineural hearing loss primarily affecting the mid-frequencies.

Amino Acid Sequence↗