Novel HOXA13 Mutations and the Phenotypic Spectrum of Hand-Foot-Genital Syndrome

Abstract

Hand-foot-genital syndrome (HFGS) is a rare, dominantly inherited condition affecting the distal limbs and genitourinary tract. A nonsense mutation in the homeobox of HOXA13 has been identified in one affected family, making HFGS the second human syndrome shown to be caused by a HOX gene mutation. We have therefore examined HOXA13 in two new and four previously reported families with features of HFGS. In families 1, 2, and 3, nonsense mutations truncating the encoded protein N-terminal to or within the homeodomain produce typical limb and genitourinary abnormalities; in family 4, an expansion of an N-terminal polyalanine tract produces a similar phenotype; in family 5, a missense mutation, which alters an invariant domain, produces an exceptionally severe limb phenotype; and in family 6, in which limb abnormalities were atypical, no HOXA13 mutation could be detected. Mutations in HOXA13 can therefore cause more-severe limb abnormalities than previously suspected and may act by more than one mechanism.

Suppression of invasive characteristics by antisense introduction of overexpressed HOX genes in ovarian cancer cells

“…HOXA10 is associated with the female reproductive system in the response to sex steroids (44,45) and invasion of breast cancer cells by regulation of p53 (37). Mutation of HOXA13 is the cause of the rare inherited disease, hand-food-genital syndrome (46). HOXB13, has been shown to be involved in differentiation of the epidermal tissue and wound healing (47,48), and has been reported to be important for prostate development (49).…”

AHOXA13 allele with a missense mutation in the homeobox and a dinucleotide deletion in the promoter underlies Guttmacher syndrome

“…The combination of hypoplastic thumbs and halluces, 5 th finger clinobrachydactyly and hypospadias also occurs in patients with typical HFGS caused by different nonsense mutations in HOXA13 (Mortlock and Innis, 1997;Goodman et al, 2000), which probably result in functional haploinsufficiency for HOXA13. A similar clinical picture has been observed in a patient hemizygous for a chromosomal deletion that removes the entire HOXA gene cluster, including HOXA13 (Devriendt et al, 1999).…”

“…We sequenced the HOXA13 genes in II.2, III.3 and III.4. The entire coding portion of the gene and the region immediately upstream of the initiator methionine were amplified by PCR from genomic DNA (Goodman et al, 2000). Both strands of PCR products were cycle sequenced, either directly or after cloning into pCRScript (Stratagene), and analysed on an ABI377 automated sequencer by two independent labs.…”

“…However, two of its features, postaxial polydactyly of the hands and short or uniphalangeal 2 nd toes with absent nails, have never been observed in HFGS patients. HFGS is now known to be caused by mutations in the HOXA13 gene (Mortlock and Innis, 1997;Goodman et al, 2000;MIM#142959; GenBank sequences of human HOXA13 [Accession Number U82827]). Therefore, we re-investigated the family described by Guttmacher ( Fig.…”

Molecular genetic cascades for external genitalia formation: An emerging organogenesis program

“…Both Hoxa-13 and Hoxd-13 are strongly expressed in the mesenchyme of the GT (Warot et al, 1997). One interesting recent finding is the "similar" hypoplasia or agenesis phenotypes of the limb and external genitalia in such affected patients of Hand-Foot-Genital Syndrome (Table 2; Goodman et al, 2000). Some Hox gene mutations affect the development of the distal (cloaca) portion of the hindgut and the GT (Tables 1, 2; Kondo et al, 1996;de Santa Barbara and Roberts, 2002).…”