Mutations in the homeodomain of HOXD13 cause syndactyly type 1-c in two Chinese families.
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.


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.
Department of Medical Genetics, College of Basic Medical Sciences, Third Military Medical University, Chongqing, China.
Limeng
L
Dai
Department of Medical Genetics, College of Basic Medical Sciences, Third Military Medical University, Chongqing, China.
Dan
D
Liu
Department of Medical Genetics, College of Basic Medical Sciences, Third Military Medical University, Chongqing, China.
Min
M
Song
Department of Medical Genetics, College of Basic Medical Sciences, Third Military Medical University, Chongqing, China.
Xueqing
X
Xu
Department of Thoracic and Cardiac Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China.
Gang
G
Xiong
Department of Thoracic and Cardiac Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China.
Kang
K
Yang
Department of Medical Genetics, College of Basic Medical Sciences, Third Military Medical University, Chongqing, China.
Kun
K
Zhang
Department of Medical Genetics, College of Basic Medical Sciences, Third Military Medical University, Chongqing, China.
Hui
H
Meng
Department of Medical Genetics, College of Basic Medical Sciences, Third Military Medical University, Chongqing, China.
Hong
H
Guo
Department of Thoracic and Cardiac Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China.
Yun
Y
Bai
D044466:Asian People / Q000235:genetics*; D002681:China; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D013576:Syndactyly / Q000235:genetics* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics*
C513184:HOXD13 protein, human; D018398:Homeodomain Proteins; D014157:Transcription Factors