[email protected] (受疫情影响,东南亚目前只开放曼谷诊所)
全周 (9AM - 5PM)

我们和你在一起

Extra info thumb
  • 总部: 泰国曼谷市巴吞汪区仑披尼分区 普勒吉路齐隆巷5号.
  • [email protected]
DEAFNESS, AUTOSOMAL RECESSIVE 3; DFNB3

DEAFNESS, AUTOSOMAL RECESSIVE 3; DFNB3

Alternative titles; symbolsNEUROSENSORY NONSYNDROMIC RECESSIVE DEAFNESS 3; NSRD3▼ Clinical FeaturesFriedman et al. (1995) reported that 2% of the residents of Be...

Alternative titles; symbols

  • NEUROSENSORY NONSYNDROMIC RECESSIVE DEAFNESS 3; NSRD3

▼ Clinical Features
Friedman et al. (1995) reported that 2% of the residents of Bengkala, an Indonesian village on the north shore of Bali, have profound, congenital, neurosensory, nonsyndromal deafness due to an autosomal recessive mutation at a locus designated DFNB3 (for the third autosomal recessive, nonsyndromic deafness locus to be mapped). This remote village dates to at least the 13th century as documented by charters inscribed in Sanskrit on metallic plates. Of the 2,185 residents, 47 had profound deafness of the type described. As an adaptation to the high percentage of deaf individuals, the citizens of Bengkala had developed a unique sign language used by most of the hearing persons as well as the deaf villagers. Deaf couples produced all deaf progeny. In 4- and 5-generation Bengkala kindreds, 2 of which were illustrated, there were no consanguineous marriages. The deaf individuals had no apparent vestibular abnormalities or dysmorphic features.

▼ Mapping
Friedman et al. (1995) used a direct genomewide disequilibrium search strategy, allele-frequency-dependent homozygosity mapping (AHM), and analysis of historical recombinants to map DFNB3 and position the locus relative to flanking markers. They found that DFNB3 maps to chromosome 17. In individuals homozygous for DFNB3, historical recombinant phenotypes for the flanking markers D17S122 and D17S783 placed DFNB3 in a 5.3-cM interval of the pericentromeric region of chromosome 17 (17p12-q12).

With new short tandem repeats (STRs) from the DFNB3 region and additional DNA samples from affected individuals from Bengkala, Bali, Liang et al. (1997, 1998) found 2 historical recombinants for marker D17S953 from the telomeric side of 17p11.2 and 5 historical recombinants for marker D17S2201 on the centromeric side of 17p11.2. These recombinants further delimited the DFNB3 critical region to less than 4 cM within the Smith-Magenis syndrome common deletion region (182290), for which there were good physical maps. Liang et al. (1997, 1998) also had evidence that mutations in DFNB3 are responsible for recessive deafness outside of Bali. Nonsyndromic congenital recessive deafness in 2 unrelated consanguineous families in India were also linked to the DFNB3 region. The haplotypes of affected individuals in these 2 Indian families were different from each other and different from the Bengkala haplotype, suggesting that these 3 DFNB3 mutations arose independently.

▼ Population Genetics
Winata et al. (1995) studied further the congenital deafness prevalent in the Bengkala village population. They estimated the frequency of the DFNB3 mutant allele to be 9.4% among hearing people, who have a 17.2% chance of being heterozygotes.

▼ Molecular Genetics
In a large multigenerational consanguineous Brazilian pedigree with prelingual severe to profound sensorineural deafness, negative for mutations in the deafness-associated GJB2 (121011) and GJB6 (604418) genes and for the A1555G mitochondrial mutation in the MTRNR1 gene (561000.0001), Lezirovitz et al. (2008) identified unexpected genetic heterogeneity: 15 affected individuals from 'branch 2' of the family were homozygous for a 1-bp deletion (10573delA; 602666.0012) in the MYO15A gene, whereas 4 affected sibs from 'branch 1' and 1 individual from 'branch 2' were compound heterozygous for 10573delA and a 4-bp deletion (602666.0013) in MYO15A. In 1 patient, only the 10573delA mutation could be identified. No mutations in MYO15A were identified in 5 patients from 2 additional branches of the family: the 3 mutation-negative patients from 'branch 4' of the family had a distinct clinical presentation, with 2 having mental retardation and 1 a mixed hearing loss, whereas the 2 mutation-negative patients from 'branch 3' had a phenotype similar to that of their mutation-positive relatives.

▼ Animal Model
Liang et al. (1998) proposed, on the basis of conserved synteny, that the recessive mouse deafness mutations 'shaker-2' (sh2) and sh2(j) are models of DFNB3. Genetic mapping of sh2 refined the location to a 0.6-cM interval of mouse chromosome 11. Three homologous genes map within the sh2 and DFNB3 intervals, suggesting that sh2 is the homolog of DFNB3.

Probst et al. (1998) demonstrated that deafness in shaker-2 mice was corrected by a bacterial artificial chromosome (BAC) transgene containing the unconventional myosin XVA (MYO15A; 602666). Because of its location in a region of homology of synteny to 17p, shaker-2 was thought to be the homolog of DFNB3. Wang et al. (1998) demonstrated that this was indeed the case by finding mutations of MYO15A in consanguineous Bengkala and Indian families.

Anderson et al. (2000) described the shaker-2(J) lesion, which is a 14.7-kb deletion that removes the last 6 exons from the 3-prime terminus of the Myo15 transcript.

Tags: 17p11.2