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HOXD13, the most 5' gene of the HOXD cluster, encodes a homeodomain transcription factor with important functions in limb patterning and growth. Heterozygous mutations of human HOXD13, encoding polyalanine expansions or frameshifts, are believed to act by dominant negative or haploinsufficiency mechanisms and are predominantly associated with synpolydactyly phenotypes. Here, we describe two mutations of HOXD13 (923C-->G encoding Ser308Cys and 940A-->C encoding Ile314Leu) that cause missense substitutions within the homeodomain. Both are associated with distinctive limb phenotypes in which brachydactyly of specific metacarpals, metatarsals, and phalangeal bones is the most constant feature, exhibiting overlap with brachydactyly types D and E. We investigated the binding of synthetic mutant proteins to double-stranded DNA targets in vitro. No consistent differences were found for the Ser308Cys mutation compared with the wild type, but the Ile314Leu mutation (which resides at the 47th position of the homeodomain) exhibited increased affinity for a target containing the core recognition sequence 5'-TTAC-3' but decreased affinity for a 5'-TTAT-3' target. Molecular modeling of the Ile314Leu mutation indicates that this mixed gain and loss of affinity may be accounted for by the relative positions of methyl groups in the amino acid side chain and target base.

Original publication

DOI

10.1086/374721

Type

Journal article

Journal

American journal of human genetics

Publication Date

04/2003

Volume

72

Pages

984 - 997

Addresses

Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, and Department of Plastic and Reconstructive Surgery, Radcliffe Infirmary, Oxford, United Kingdom.

Keywords

Leg, Arm, Fingers, Humans, Synostosis, Homeodomain Proteins, Transcription Factors, DNA Primers, Polymerase Chain Reaction, Pedigree, Sequence Alignment, Binding Sites, Amino Acid Sequence, Base Sequence, Sequence Homology, Amino Acid, Mutation, Missense, Molecular Sequence Data, Female, Male