Mutations in the Homeodomain of HOXD13 Cause Syndactyly Type 1-c in Two Chinese FamiliesReport as inadecuate




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Background

Syndactyly type 1 SD1 is an autosomal dominant limb malformation characterized in its classical form by complete or partial webbing between the third and fourth fingers and-or the second and third toes. Its four subtypes a, b, c, and d are defined based on variable phenotypes, but the responsible gene is yet to be identified. SD1-a has been mapped to chromosome 3p21.31 and SD1-b to 2q34–q36. SD1-c and SD1-d are very rare and, to our knowledge, no gene loci have been identified.

Methods and Results

In two Chinese families with SD1-c, linkage and haplotype analyses mapped the disease locus to 2q31-2q32. Copy number variation CNV analysis, using array-based comparative genomic hybridization array CGH, excluded the possibility of microdeletion or microduplication. Sequence analyses of related syndactyly genes in this region identified c.917G>A p.R306Q in the homeodomain of HOXD13 in family A. Analysis on family B identified the mutation c.916C>G p.R306G and therefore confirmed the genetic homogeneity. Luciferase assays indicated that these two mutations affected the transcriptional activation ability of HOXD13. The spectrum of HOXD13 mutations suggested a close genotype-phenotype correlation between the different types of HOXD13-Syndactyly. Overlaps of the various phenotypes were found both among and within families carrying the HOXD13 mutation.

Conclusions

Mutations p.R306Q and p.R306G in the homeodomain of HOXD13 cause SD1-c. There are affinities between SD1-c and synpolydactyly. Different limb malformations due to distinct classes of HOXD13 mutations should be considered as a continuum of phenotypes and further classification of syndactyly should be done based on phenotype and genotype.



Author: Limeng Dai, Dan Liu, Min Song, Xueqing Xu, Gang Xiong, Kang Yang, Kun Zhang, Hui Meng, Hong Guo , Yun Bai

Source: http://plos.srce.hr/



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