Mutation data of the MITF gene in Waardenburg syndrome

Mutation type*1 Mutation position Length of affected nucleotides Nucleotide sequence after mutation Mutation name Case # Consequence Disease Position Pathological? Clinical Feature 1 (Dystopia canthorum) Clinical Feature 2 Hereditary Pattern Ethnic Origin Reference
S 33+1 1 A 33+1G->A 1 ntd 33+1 G-A -> splice doner site change after codon 51, termination in the intron 18 codons downstream WS2*2 intron 1 (doner site)   Absence of dystopia (The W index was 1.28-1.94, mean 1.68) Various combination of hearing loss, heterochromia irides, white forelock and early greying in the affected family members. AD*6 South Australia Tassabehji,M. et al. Nat Genet 8,251(1994)
S 442-2 1 C 442-2A->C 1 ntd 442-2 A-C -> splice acceptor site change after codon 187, skipping of exon 5, frameshift and termination at the 3' end of exon 6 (position 211) WS2 intron 4 (acceptor site)   Absence of dystopia (The W index was 1.71-1.98, mean 1.81) Hearing loss and white forelock. (All 8 affected family members have sensorineural hearing loss; 3 white forelocks before early greying; 1 white skin patches and 1 heterochromia irides; 3 thin hair. a feature not generally associated with WS) AD South England Tassabehji,M. et al. Nat Genet 8,251(1994)
S 33+1 1 A 33+1G->A 1 ntd 33+1 G-A -> splice doner site change after codon 51, termination in the intron 18 codons downstream WS2 intron 1 (doner site)   (Absence of dystopia) two of: congenital sensorineural hearing loss, iris pigmentary disturbance, white forelock or greying before age 30 AD South Australia Tassabehji,M. et al. Hum Mol Genet 4,2131(1995)
D 649 3   649delAGA 1 3-bp del AGA at ntd 649 -> del of Arg at codon 217 WS (more resemble Tietz albuminism-deafness syndrome) exon 7 (basic domain)   Face was normal and there was no dystopia canthorum. severe congenital sensorineural hearing loss, red hair (blond/grey at the age of 16), pale skin with numerous orange freckles, blue eyes and the irides did not transilluminate, but lack of retinal pigmentation. AD ND Tassabehji,M. et al. Hum Mol Genet 4,2131(1995)
M 748 1 C S250P 1 TCC-CCC at ntd 748 -> Ser-Pro at codon 250 (unclassified) WS*3 exon 8 (helix 2 of HLH)   (insufficient clinical information to judge dystopia) unilateral hearing loss and premature greying, shortened fifth fingers and, on the left side, a nail half of which grown black. AD ND Tassabehji,M. et al. Hum Mol Genet 4,2131(1995)
M 832 1 G N278D 1 AAC-GAC at ntd 832 -> Asn-Asp at codon 278 WS2 exon 8 (ZIP)   (Absence of dystopia) sensorial hearing loss and heterochromia. The only relevant family history is that a deceased cousin of the father was said to have had a white forelock in his teens. AD ND Tassabehji,M. et al. Hum Mol Genet 4,2131(1995)
M 892 1 C S298P 1 TCC-CCC at ntd 892 -> Ser-Pro at codon 298 WS2 exon 9 (3' of ZIP)   (Absence of dystopia) two of: congenital sensorineural hearing loss, iris pigmentary disturbance, white forelock or greying before age 30, The family has a 3-generation history of WS2. AD ND Tassabehji,M. et al. Hum Mol Genet 4,2131(1995)
P -36 1 A -36 G->A 1 G-A transition at position -36 relative to the ATG start codon (unclassified) WS exon 1 (5'UT) Likely non-pathological change (insufficient clinical information to judge dystopia) Cases with 2 of the hearing or pigmentary criteria for WS1 or 2, but with insufficient clinical information to judge the presence or absence of dystopia AD ND Tassabehji,M. et al. Hum Mol Genet 4,2131(1995)
P 345+13 1 C 345+13 G->C 1 ntd 345+13 G-C WS (more resemble Tietz albuminism-deafness syndrome) intron 3 Likely non-pathological change   Individuals or families with auditory and/or pigmentary symptoms probably different from WS, but with no features suggesting wider neural crest involvement. These included families with isolated heterochromia, single individuals with premature greying an AD ND Tassabehji,M. et al. Hum Mol Genet 4,2131(1995)
P 608 1 A R203K 1 AGG-AAG at ntd 608 -> Arg-Lys at codon 203 WS2 exon 6 (basic domain) Likely non-pathological change (Absence of dystopia) Absence of dystopia plus two of: congenital sensorineural hearing loss, iris pigmentary disturbance, white forelock or greying before age 30,　The family has a 4-generation history of typical domain Type 2 WS. AD ND Tassabehji,M. et al. Hum Mol Genet 4,2131(1995)
P 710+14 1 G 710+14 C->G 1 ntd 710+14 C-G WS1*4 intron 7 Likely non-pathological change (Dystopia canthorum) one of: congenital sensorineural haring loss >25 dB, iris pigmentary abnormality (excluding blue eyes in white persons), white forelock AD ND Tassabehji,M. et al. Hum Mol Genet 4,2131(1995)
P 710+28 1 C 710+28 T->C 1 ntd 710+28 T-C (unclassified) WS intron 7 Likely non-pathological change (insufficient clinical information to judge dystopia) Cases with 2 of the hearing or pigmentary criteria for WS1 or 2, but with insufficient clinical information to judge the presence or absence of dystopia AD ND Tassabehji,M. et al. Hum Mol Genet 4,2131(1995)
P 710+28 1 C 710+28 T->C 1 ntd 710+28 T-C WS2 intron 7 Likely non-pathological change (Absence of dystopia) two of: congenital sensorineural hearing loss, iris pigmentary disturbance, white forelock or greying before age 30 AD ND Tassabehji,M. et al. Hum Mol Genet 4,2131(1995)
P 710+31 1 C 710+31 T->C 1 ntd 710+31 T-C (probable) WS2*5 intron 7 Likely non-pathological change   The family history showed hearing loss plus one or more WS2 criteria, in a pattern compatible with dominant inheritance, but no one individual had more than one feature AD ND Tassabehji,M. et al. Hum Mol Genet 4,2131(1995)
N 640 1 T R214X 1 CGA-TGA at ntd 640 -> Arg-Stop at codon 214, trancated protein lacking HLH-Zip structure WS2 exon 7   None of the family members showed dystopia canthorum. sensori-neural hearing loss, heterochromia irides, white forelock, and early graying. AD Nothrn European Nobukuni,V. et al. Am J Hum Genet 59,76(1996)
N 775 1 T R259X 1 CGA-TGA at ntd 775 -> Arg-Stop at codon 259, trancated protein lacking Zip structure WS2 exon 8   None of the family members showed dystopia canthorum. sensori-neural hearing loss, heterochromia irides, white forelock, and early graying. AD various Nobukuni,V. et al. Am J Hum Genet 59,76(1996)
N 640 1 T R214X 1 CGA-TGA at ntd 640 -> Arg-Stop at codon 214, trancated protein lacking HLH-Zip WS2 exon 7   absent of dystopia conthorum (W index <2.07) sensorineural hearing loss, heterochromia iridis, premature graying and white forelock. AD South India Lalwani, AK. Et al. Am J Med Genet 80, 406(1998)
FD 824 1   824delA 1 1-bp del A at ntd 824 (codon 275) -> frameshift and a TGA termination in exon 9 WS2 exon 8     The affected individuals were also either homozygous or heterozygous for the arg402-to-gln polymorphism of the tyrosinase gene(TYR). TYR gene is controlled by the MITF. AD various*7 Morell, R. et al. Hum Mol Genet 6, 659(1997)

*1 Abbreviations are as follows: M, Missense; S, Splicing; D, Deletion; P, Polymorphism; N, Nonsense; FD, Frameshift Deletion.
*2 WS2 : Absence of dystopia plus two of: congenital sensorineural hearing loss, iris pigmentary disturbance, white forelock or greying before age 30.
*3 Unclassified WS : Cases with 2 of the hearing or pigmentary criteria for WS1 or 2, but with insufficient clinical information to judge the presence or absence of dystopia.
*4 WS1 : Dystopia canthorum plus one of: congenital sensorineural haring loss >25 dB, iris pigmentary abnormality (excluding blue eyes in white persons), white forelock.
*5 Probable WS2 : The family history showed hearing loss plus one or more WS2 criteria, in a pattern compatible with dominant inheritance, but no one individual had more than one feature.
*6 Abbreviations are as follows: AD, Autosomal Dominant; ND, Not Described.
*7: The 134 unrelated individuals or families came from the UK, Germany (7), the Czech Republic (3), Poland (2), Australia (3), the Netherland (2), Italy (2), Canada (1), and Denmark (2).







Last updated 29 March 2000