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.

Syndactyly: phenotypes, genetics and current classification

“…Type V syndactyly is inherited as an autosomal dominant entity, and it has been attributed to a missense mutation in homeodomain of HOXD13 in a Chinese family. 40 Syndactyly type VI (Mitten type; fusion of 2/5 fingers and 2/3 toes) Temtamy and McKusick 3 described a family in which the index subject had fusion of fingers from second to fifth in his right hand, whereas distal and terminal phalanges were amalgamated in a knot-like structure (Figure 2). The feet showed syndactyly involving second and third toes.…”

Etiology of Caudal Regression Syndrome

“…Although mutations in SHH and GLI3 are associated with human syndromes that may include ARM as part of the phenotypic spectrum, such as holoprosencephaly type 3 (OMIM #142945) and Pallister-Hall syndrome (OMIM #146510), SHH and GLI3 mutations have not been identified in CRS. However, mutations in the human HOXD13 gene, which is an SHH target during gut morphogenesis, are associated with limb malformations, including synpolydactyly 1 (SPD1; OMIM #186000), brachydactyly types D (BDD; OMIM #113200) and E (BDE; OMIM #113300), syndactyly type V (OMIM #186300), and a novel brachydactyly-syndactyly syndrome [65]. Thus, HOXD13 may not only be implicated in limb malformations, but also in the development of gut and genitourinary structures.…”

Distinct global shifts in genomic binding profiles of limb malformation-associated HOXD13 mutations

“…In these cases the phenotypes can be mutation specific, as it has been reported for, e.g., MSX2, FOXC1, PITX2, or HOXD13 (Kozlowski and Walter 2000;Wilkie et al 2000;Johnson et al 2003;Saleem et al 2003). How these mutations exert their effect remains unclear, but it is likely that the mutant protein has altered binding specificity or affinity, resulting in abnormal targets or activity (Caronia et al 2003;Saleem et al 2003;Zhao et al 2007).…”