THE MUTATIONAL SPECTRUM IN WAARDENBURG SYNDROME

被引:176
作者
TASSABEHJI, M
NEWTON, VE
LIU, XZ
BRADY, A
DONNAI, D
KRAJEWSKAWALASEK, M
MURDAY, V
NORMAN, A
OBERSZTYN, E
REARDON, W
RICE, JC
TREMBATH, R
WIEACKER, P
WHITEFORD, M
WINTER, R
READ, AP
机构
[1] ST MARYS HOSP,DEPT MED GENET,MANCHESTER M13 0JH,LANCS,ENGLAND
[2] UNIV MANCHESTER,CTR AUDIOL,MANCHESTER M13 9PL,LANCS,ENGLAND
[3] UNIV LONDON ST GEORGES HOSP,SCH MED,DEPT CLIN GENET,LONDON SW17 0RE,ENGLAND
[4] MEM HOSP WARSAW,CTR CHILD HLTH,DEPT GENET,WARSAW,POLAND
[5] BIRMINGHAM MATERN HOSP,CLIN GENET UNIT,BIRMINGHAM B15 2TG,W MIDLANDS,ENGLAND
[6] INST MOTHER & CHILD HLTH,WARSAW,POLAND
[7] INST CHILD HLTH,LONDON WC1N 1EH,ENGLAND
[8] WOMENS & CHILDRENS HOSP,DEPT EAR NOSE & THROAT SURG,ADELAIDE,SA 5006,AUSTRALIA
[9] LEICESTER ROYAL INFIRM,CLIN GENET SERV,LEICESTER LE1 5WW,LEICS,ENGLAND
[10] UNIV MAGDEBURG,INST HUMAN GENET,D-39120 MAGDEBURG,GERMANY
[11] DUNCAN GUTHRIE INST MED GENET,GLASGOW G3 8SJ,LANARK,SCOTLAND
基金
英国惠康基金;
关键词
D O I
10.1093/hmg/4.11.2131
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
One hundred and thirty-four families or individuals with auditory-pigmentary syndromes such as Waardenburg syndrome (WS) or probable neuro-cristopathies were screened for mutations in the PAX3 and MITF genes. PAX3 mutations were found in 20/25 families with definite Type 1 WS and 1/2 with Type 3 WS, but in none of 23 with definite Type 2 WS or 36 with other neurocristopathies. The PAX3 mutations included substitutions of conserved amino acids in the paired domain or the homeodomain, splice-site mutations, nonsense mutations and frameshifting insertions or deletions. No phenotype-genotype correlations were noted within WS1 families. With MITF, mutations likely to affect protein function were found in seven families, five of which had definite Type 2 WS. We conclude that Type 1 and Type 3 WS are allelic and are normally caused by loss of function mutations in PAX3; that Type 2 WS is heterogeneous, with about 20% of cases caused by mutations in MITF, and that individuals with auditory, pigmentary or neural crest syndromes which do not fit stringent definitions of Waardenburg syndrome are unlikely to have mutations in either the PAX3 or MITF genes. The molecular pathology of MITF/microphthalmia mutations appears to be different in humans and mice, with gene dosage having more significant effects in humans than in the mouse.
引用
收藏
页码:2131 / 2137
页数:7
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