Missense Mutations in the Homeodomain of HOXD13 Are Associated with Brachydactyly Types D and E

Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, and Department of Plastic and Reconstructive Surgery, Radcliffe Infirmary, Oxford, United Kingdom.
The American Journal of Human Genetics (Impact Factor: 10.93). 04/2003; 72(4):984-97. DOI: 10.1086/374721
Source: PubMed


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.

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    • "Three LOF-alleles, R31G, R31Q, and R31W, cause a SPD phenotype, with incomplete penetrance in the case of R31G and R31W [Debeer et al., 2002; Dai et al., 2014]. The four remaining missense mutations are GOF-alleles and do not cause SPD, but Brachydactyly type E and D (S41C and I47L), Syndactyly Type V (Q50R), and a complex brachydactyly-syndactyly phenotype (Q50K) [Caronia et al., 2003; Johnson et al., 2003; Zhao et al., 2007; Ibrahim et al., 2013]. "
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    ABSTRACT: Synpolydactyly (SPD) is a rare congenital limb disorder characterized by syndactyly between the third and fourth fingers and an additional digit in the syndactylous web. In most cases SPD is caused by heterozygous mutations in HOXD13 resulting in the expansion of a N-terminal polyalanine tract. If homozygous, the mutation results in severe shortening of all metacarpals and phalanges with a morphological transformation of metacarpals to carpals. Here, we describe a novel homozygous missense mutation in a family with unaffected consanguineous parents and severe brachydactyly and metacarpal-to-carpal transformation in the affected child. We performed whole exome sequencing on the index patient, followed by Sanger sequencing of parents and patient to investigate cosegregation. The DNA-binding ability of the mutant protein was tested with electrophoretic mobility shift assays. We demonstrate that the c.938C>G (p.313T>R) mutation in the DNA-binding domain of HOXD13 prevents binding to DNA in vitro. Our results show to our knowledge for the first time that a missense mutation in HOXD13 underlies severe brachydactyly with metacarpal-to-carpal transformation. The mutation is non-penetrant in heterozygous carriers. In conjunction with the literature we propose the possibility that the metacarpal-to-carpal transformation results from a homozygous loss of functional HOXD13 protein in humans in combination with an accumulation of non-functional HOXD13 that might be able to interact with other transcription factors in the developing limb. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Nov 2015 · American Journal of Medical Genetics Part A
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    • "Zhao et al., 2007). For those mutations, a mixed gain-and loss-offunction mechanism has been proposed as an explanation for the complex overlapping limb malformation phenotypes (Johnson et al., 2003; Zhao et al., 2007). "
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    ABSTRACT: Synpolydactyly (SPD, OMIM 186000) is a rare congenital limb disorder characterized by syndactyly between the third and fourth fingers and between the fourth and fifth toes, with partial or complete digit duplication in the syndactylous web. The majority of these anomalies co-segregate with mutations in the HOXD13 gene, a homeobox transcription factor crucial for distal limb development. Different classes of HOXD13 mutations are involved in the pathogenesis of synpolydactyly, but an unequivocal genotype-phenotype correlation cannot always be achieved due to the clinical heterogeneity and reduced penetrance of SPD. All mutations identified so far mapped to the N-terminal polyalanine tract or to the C-terminal homeodomain of HOXD13, causing typical or atypical features of SPD respectively. However, mutations outside of these domains cause a broad variety of clinical features that complicate the differential diagnosis. The existing animal models that are currently used to study HOXD13 (mal)function are therefore instrumental in unraveling potential genotype-phenotype correlations. Both mouse- and chick-based approaches allow the in vivo study of the pathogenic mechanism by which HOXD13 mutations cause SPD phenotypes as well as help in identifying the transcriptional targets. Developmental Dynamics, 2013. © 2013 Wiley Periodicals, Inc.
    Full-text · Article · Feb 2014 · Developmental Dynamics
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    • "Regarding BDE caused by mutations in HOXD13, the pattern profile showed many variations between affected patients: most of them had shortening of metacarpals III and sometimes also IV and V (Figure 1A); and in the feet, shortening of the metatarsals IV was frequently seen, sometimes in combination with that of metatarsals I, III or V and broadening of the hallux (Figure 1B). In addition, little-finger distal phalanx hypoplasia/aplasia, lateral phalangeal duplication and/or clinodactyly of finger IV, and syndactyly of fingers III/IV were frequently observed [9,11,13]. Finally, in general, affected individuals had normal stature and no appreciable psychomotor developmental delay (Additional file 1: Table S2) [9,11,13,14]. "
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    ABSTRACT: Brachydactyly (BD) refers to the shortening of the hands, feet or both. There are different types of BD; among them, type E (BDE) is a rare type that can present as an isolated feature or as part of more complex syndromes, such as: pseudohypoparathyroidism (PHP), hypertension with BD or Bilginturan BD (HTNB), BD with mental retardation (BDMR) or BDE with short stature, PTHLH type. Each syndrome has characteristic patterns of skeletal involvement. However, brachydactyly is not a constant feature and shows a high degree of phenotypic variability. In addition, there are other syndromes that can be misdiagnosed as brachydactyly type E; some of which will also be discussed. The objective of this review is to describe some of the syndromes in which BDE is present, focusing on clinical, biochemical and genetic characteristics as features of differential diagnoses, with the aim of establishing an algorithm for their differential diagnosis. As in our experience, many of these patients are recruited at Endocrinology and/or Pediatric Endocrinology Services due to their short stature, we have focused the algorithm in those steps that could mainly help these professionals.
    Full-text · Article · Sep 2013 · Orphanet Journal of Rare Diseases
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