title: Mutations in HOXD13 underlie syndactyly type V and a novel brachydactyly-syndactyly syndrome.
abstract: HOXD13, the homeobox-containing gene located at the most 5' end of the HOXD cluster, plays a critical role in limb development. It has been shown that mutations in human HOXD13 can give rise to limb malformations, with variable expressivity and a wide spectrum of clinical manifestations. Polyalanine expansions in HOXD13 cause synpolydactyly, whereas amino acid substitutions in the homeodomain are associated with brachydactyly types D and E. We describe two large Han Chinese families with different limb malformations, one with syndactyly type V and the other with limb features overlapping brachydactyly types A4, D, and E and mild syndactyly of toes 2 and 3. Two-point linkage analysis showed LOD scores >3 (theta =0) for markers within and/or flanking the HOXD13 locus in both families. In the family with syndactyly type V, we identified a missense mutation in the HOXD13 homeodomain, c.950A-->G (p.Q317R), which leads to substitution of the highly conserved glutamine that is important for DNA-binding specificity and affinity. In the family with complex brachydactyly and syndactyly, we detected a deletion of 21 bp in the imperfect GCN (where N denotes A, C, G, or T) triplet-containing exon 1 of HOXD13, which results in a polyalanine contraction of seven residues. Moreover, we found that the mutant HOXD13 with the p.Q317R substitution was unable to transactivate the human EPHA7 promoter. Molecular modeling data supported these experimental results. The calculated interactions energies were in agreement with the measured changes of the activity. Our data established the link between HOXD13 and two additional limb phenotypes--syndactyly type V and brachydactyly type A4--and demonstrated that a polyalanine contraction in HOXD13, most likely, led to other digital anomalies but not to synpolydactyly. We suggest the term "HOXD13 limb morphopathies" for the spectrum of limb disorders caused by HOXD13 mutations.
authors.affiliation: Department of Medical Genetics and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing China.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Zhao
authors.forename: Miao
authors.initials: M
authors.lastname: Sun
authors.forename: Jin
authors.initials: J
authors.lastname: Zhao
authors.forename: J Alfonso
authors.initials: JA
authors.lastname: Leyva
authors.forename: Hongwen
authors.initials: H
authors.lastname: Zhu
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.forename: Xuan
authors.initials: X
authors.lastname: Zeng
authors.forename: Yang
authors.initials: Y
authors.lastname: Ao
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
authors.forename: Guoyang
authors.initials: G
authors.lastname: Liu
authors.forename: Wilson H Y
authors.initials: WH
authors.lastname: Lo
authors.forename: Ethylin Wang
authors.initials: EW
authors.lastname: Jabs
authors.forename: L Mario
authors.initials: LM
authors.lastname: Amzel
authors.forename: Xiangnian
authors.initials: X
authors.lastname: Shan
authors.forename: Xue
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000409:Alanine / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D010375:Pedigree; D011401:Promoter Regions, Genetic; D036141:Receptor, EphA7 / Q000235:genetics; D013576:Syndactyly / Q000235:genetics*; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation
chemical_list: C513184:HOXD13 protein, human; D018398:Homeodomain Proteins; D014157:Transcription Factors; D036141:Receptor, EphA7; D000409:Alanine