A novel ZRS mutation leads to preaxial polydactyly type 2 in a heterozygous form and Werner mesomelic syndrome in a homozygous form.
Point mutations in the zone of polarizing activity regulatory sequence (ZRS) are known to cause human limb malformations. Although most mutations cause preaxial polydactyly (PPD), triphalangeal thumb (TPT) or both, a mutation in position 404 of the ZRS causes more severe Werner mesomelic syndrome (WMS) for which malformations include the distal arm or leg bones in addition to the hands and/or feet. Of more than 15 reported families with ZRS mutations, only one homozygous individual has been reported, with no change in phenotype compared with heterozygotes. Here, we describe a novel point mutation in the ZRS, 402C>T (AC007097.4:g.105548C>T), that is transmitted through two Mexican families with one homozygous individual. The homozygous phenotype for this mutation, WMS, is more severe than the numerous heterozygous individuals genotyped from both families who have TPT and PPD. A mouse transgenic enhancer assay shows that this mutation causes an expansion of the enhancer's expression domain in the developing mouse limb, confirming its pathogenicity. Combined, our results identify a novel ZRS mutation in the Mexican population, 402C>T, and suggest that a dosage effect exists for this ZRS mutation.
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California; Institute for Human Genetics, University of California San Francisco, San Francisco, California.
Julia E
JE
VanderMeer
Reymundo
R
Lozano
Miao
M
Sun
Yuan
Y
Xue
Donna
D
Daentl
Ethylin Wang
EW
Jabs
William R
WR
Wilcox
Nadav
N
Ahituv
D000818:Animals; D001483:Base Sequence; D005260:Female; D018628:Gene Dosage; D005838:Genotype; D006228:Hand Deformities, Congenital / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008800:Mexico; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D017689:Polydactyly / Q000235:genetics* / Q000473:pathology; D013933:Thumb / Q000002:abnormalities*
C485955:LMBR1 protein, human; D008565:Membrane Proteins
SHH; Werner mesomelic syndrome; ZRS; enhancer; preaxial polydactyly