Alternative titles; symbols
HGNC Approved Gene Symbol: HOXA13
SNOMEDCT: 702425002, 722452004;
Cytogenetic location: 7p15.2 Genomic coordinates (GRCh38) : 7:27,194,364-27,200,091 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7p15.2 | ?Guttmacher syndrome | 176305 | Autosomal dominant | 3 |
| Hand-foot-genital syndrome | 140000 | Autosomal dominant | 3 |
For background information on homeobox genes, see HOXA7 (142950).
Mortlock and Innis (1997) determined the complete coding sequence for HOXA13.
Rinn et al. (2008) stated that fibroblasts obtained from anatomically distinct sites of human skin express genes in a site-specific manner. By microarray analysis of cultured fibroblasts derived from foot or thigh, followed by comparing gene expression profiles of primary fibroblasts from 43 anatomic sites, Rinn et al. (2008) found that HOXA13 expression was associated with distal sites and was required for activation of distal-specific gene expression, including expression of WNT5A (164975). Depletion of HOXA13 in human plantar fibroblasts reduced expression of distal-specific keratin-9 (KRT9; 607606), and KRT9 expression was rescued by addition of recombinant purified WNT5A. In situ hybridization showed that Hoxa13 and Wnt5a were spatially and temporally coexpressed in distal limb bud during mouse development. Rinn et al. (2008) concluded that HOXA13 control of WNT5A expression in distal fibroblasts can regulate site-specific epidermal differentiation.
Sheth et al. (2012) used mouse genetics to analyze how digit patterning (an iterative digit/nondigit pattern) is generated and showed that the progressive reduction in Hoxa13 and Hoxd11 (142986)-Hoxd13 (142989) genes (hereafter referred to as distal Hox genes) from the Gli3 (165240)-null background results in progressively more severe polydactyly, displaying thinner and densely packed digits. Combined with computer modeling, their results argued for a Turing-type mechanism underlying digit patterning, in which the dose of distal Hox genes modulates the digit period or wavelength. The phenotypic similarity of fish-fin endoskeleton patterns suggested that the pentadactyl state has been achieved through modification of an ancestral Turing-type mechanism.
Kherdjemil et al. (2016) showed that the mutually exclusive expression of the mouse genes Hoxa11 (142958) and Hoxa13, which had been proposed to be involved in the origin of the tetrapod limb, is required for the pentadactyl state. Kherdjemil et al. (2016) further demonstrated that the exclusion of Hoxa11 from the Hoxa13 domain relies on an enhancer that drives antisense transcription at the Hoxa11 locus after activation by Hoxa13 and Hoxd13. Finally, the authors showed that the enhancer that drives antisense transcription of the mouse Hoxa11 gene is absent in zebrafish, which, together with the largely overlapping expression of hoxa11 and hoxa13 genes reported in fish, suggested that this enhancer emerged in the course of the fin-to-limb transition. On the basis of the polydactyly that was observed after expression of Hoxa11 in distal limbs, Kherdjemil et al. (2016) proposed that the evolution of Hoxa11 regulation contributed to the transition from polydactyl limbs in stem-group tetrapods to pentadactyl limbs in extant tetrapods.
HOXA13 belongs to the cluster of homeobox genes on chromosome 7. As reviewed by Acampora et al. (1989), the homeobox region 1 includes at least 8 homeobox genes in 90 kb of DNA located on chromosome 7.
Mortlock (1996) found a mutation in the HOXA13 gene resulting in hand-foot-uterus (HFU) syndrome, also known as hand-foot-genital (HFG) syndrome (140000). Their observations were made in the family reported by Stern et al. (1970). This was the second mutation discovered in a HOX gene as the cause of a malformation; the first to be discovered was the mutation in HOXD13 (142989) as the cause of synpolydactyly (186000).
Mortlock and Innis (1997) found that affected members of an HFG syndrome family reported by Stern et al. (1970) had a mutation in the HOXA13 gene that converted a highly conserved tryptophan residue in the homeodomain to a stop codon with resulting truncation of 20 amino acids from the protein (142959.0001). It was thought that the mutation probably eliminated or greatly reduced the ability of the protein to bind to DNA.
Goodman et al. (2000) examined the HOXA13 gene in 2 new and 4 previously reported families with features of HFG syndrome. In 3 families, nonsense mutations truncating the encoded protein N-terminal to or within the homeodomain produced typical limb and genitourinary abnormalities; in the fourth family, an expansion of an N-terminal polyalanine tract produced a similar phenotype; in the fifth family, a missense mutation, which altered an invariant domain, produced an exceptionally severe limb phenotype; and in the sixth family, in which limb abnormalities were atypical, no HOXA13 mutation was detected.
The polyalanine expansion reported by Goodman et al. (2000) occurred in exon 1 following nucleotide 388 and resulting in the in-frame insertion of 24-bp and an additional 8 alanine residues (142959.0003). Utsch et al. (2002) reported a similar in-frame expansion of 6 alanines also in exon 1, following nucleotide 376, of the HOXA13 gene (142959.0006). They pointed out that expansion by 7 up to 14 alanine residues occurs in the HOXD13 gene, resulting in synpolydactyly.
Guttmacher syndrome (176305) has a number of features in common with hand-foot-genital syndrome, including hypoplastic thumbs and halluces, fifth-finger clinobrachydactyly, and hypospadias. However, 2 of its features, postaxial polydactyly of the hands and short or uniphalangeal second toes with absent nails, had never been observed in patients with hand-foot-genital syndrome. Because of the similarities, Innis et al. (2002) reinvestigated the family originally described by Guttmacher (1993). They found that affected individuals were heterozygous for a novel missense mutation in the HOXA13 homeobox (Q50L; 142959.0005), which arose on an allele already carrying a novel 2-bp deletion (involving GC at positions -78 and -79) in the gene's highly conserved promoter region. This promoter deletion produces no detectable abnormalities on its own, but may have contributed to the phenotype in the affected individuals. The missense mutation, which altered a key residue in the recognition helix of the homeodomain, is likely to perturb HOXA13's DNA-binding properties, resulting in both a loss and a specific gain of function.
Mortlock et al. (1996) found a 50-bp deletion in the first exon of the Hoxa13 gene in mice with the semidominant mutation 'Hypodactyly' (Hd). The mutation was known to map to a genetic interval overlapping the Hoxa cluster on mouse chromosome 6. They stated that the deletion probably arose from unequal recombination between triplet repeats.
Innis et al. (2004) performed homologous recombination in murine embryonic stem cells to expand the size of the third largest polyalanine tract by 10 residues. Mutant mice were indistinguishable from Hoxa13-null mice. Mutant limb buds had normal steady-state Hoxa13 RNA expression, normal mRNA splicing, and reduced levels of steady-state protein. In vitro translation efficiency of the mutant protein was normal. Innis et al. (2004) concluded that loss of function was secondary to reduced levels of the expanded protein in vivo, likely due to degradation.
Late limb buds of all tetrapods contain 3 proximodistal segments, each expressing specific homeobox genes. The stylopod (upper limb) expresses Meis1/2 (see 601739), the zeugopod (lower limb) expresses Hoxa11 (142958), and the autopod (hand/foot) Hoxa13, although none of these markers is sufficient to specify limb-segment identity (summary by Rosello-Diez et al., 2011). Cooper et al. (2011) showed that Wnt3a (606359), Fgf8 (600483), and retinoic acid act together to maintain markers of early limb mesenchyme in culture. Rosello-Diez et al. (2011) showed that the first limb bud proximodistal regionalization results from the balance between proximal and distal signals. The results of both groups suggested that retinoic acid is the trunk proximalizing signal and that the trigger for initiating the process of specification of the zeugopod and autopod is the cessation (due to displacement) of retinoic acid exposure, and argued against a mechanism linking proximodistal specification to a cell cycle-based internal clock.
Roux et al. (2019) found that mice with conditional knockout of Hoxa13 displayed megaureter phenotype due to abnormal ureter insertion caused by defective common nephric duct elimination. The severity of the hydroureter phenotype was likely associated with delayed ureter maturation in Hoxa13 mutant mice. In addition, Hoxa13 mutant mice displayed defective Mullerian duct fusion similar to that found in female patients with HFG syndrome. In situ hybridization analysis revealed that Hoxa13 acted upstream of Ret (164761) and Gata3 (131320) and impacted Ret expression through Gata3. Furthermore, Gata3 played a mediator role on Hoxa13 function in the urogenital sinus.
Mortlock and Innis (1997) found that patients with the hand-foot-genital syndrome (HFG; 140000) in the family reported by Stern et al. (1970) had an A-to-G transition in a highly conserved tryptophan codon in the HOXA13 homeodomain, which, in addition to causing a trp369-to-ter substitution (TGG to TGA), also destroyed a NlaIV restriction site. The nonsense mutation was predicted to produce a truncated protein missing 20 C-terminal amino acids based on homology to other homeodomains whose 3-dimensional structures had been determined. This portion of the normal homeodomain folds into the last of the 3 alpha-helices. This helix is critical for DNA binding. The authors noted that the tryptophan that was mutated in this family is the only amino acid which is invariant in all known homeodomain proteins.
Goodman et al. (2000) identified a nonsense truncating mutation in a male patient who had hand and foot abnormalities typical of hand-foot-genital syndrome (HFG; 140000), as well as a short penis tethered inferiorly to the scrotal sac. The predicted truncated protein in this individual lacked the entire homeodomain of the HOXA13 protein. The proband was heterozygous for an A-to-C substitution in exon 1 at base 407 (number of bases starting at the first residue of the initiated codon). The mutation converted a serine residue to a stop codon and was predicted to result in a truncated protein containing only the first 135 amino acids of the wildtype protein.
In the family (family 4) with hand-foot-genital syndrome (HFG; 140000) in multiple generations reported by Elias et al. (1978), Verp (1989), and Donnenfeld et al. (1992), Goodman et al. (2000) found that affected members were heterozygous for a 24-bp in-frame insertion in exon 1 at nucleotide 387 of the HOXA13 gene. This insertion occurred in a stretch of 18 imperfect trinucleotide repeats encoding the third of 3 N-terminal polyalanine tracts. It probably had arisen by duplication of repeats 7-14 and expanded the tract from 18 to 26 alanines (8-alanine expansion).
In an isolated case of hand-foot-genital syndrome (HFG; 140000), Goodman et al. (2000) identified a heterozygous A-to-C substitution in exon 2 at nucleotide 1114 of the HOXA13 gene, resulting in an asp51-to-his amino acid substitution. The affected individual had severe hand and foot abnormalities, including extremely short thumbs, absent halluces, and marked hypoplasia of all middle phalanges, as well as glanular hypospadias. The authors stated that this was the first missense mutation identified in a human HOX protein.
In the original family described by Guttmacher (1993) with preaxial deficiency, postaxial polydactyly, and hypospadias (Guttmacher syndrome; 176305), Innis et al. (2002) found a novel missense mutation in the HOXA13 homeobox cDNA: an A-to-T transition at position 1112A-T, producing a gln50-to-leu (Q50L) amino acid substitution in the homeodomain of the protein and arising on an allele already carrying a novel 2-bp deletion in the promoter region of the gene. The promoter deletion of GC at position -78 and -79 produces no detectable abnormalities on its own, but was thought to contribute to the phenotype in the affected individuals.
In affected members of a family (family 1) with hand-foot-genital syndrome (HFG; 140000), Utsch et al. (2002) found an 18-bp in-frame duplication after nucleotide 376 in exon 1 of the HOXA13 gene, within a cryptic trinucleotide repeat sequence encoding an 18-residue polyalanine tract, resulting in a 6-alanine expansion. The family came to attention because of an affected son admitted to hospital for correction of glanular hypospadias. He showed small hands with short thumbs, brachydactyly of the fifth fingers, and hypoplastic thenar eminences, as well as small feet with short great toes and medially deviated toes. The mother and grandmother showed the same anomalous distal limb findings. Ultrasonography visualized a uterus bicornus unicollis with double cervix in both the mother and grandmother. In addition, the mother showed a longitudinal vaginal septum, explaining the necessity for cesarean section for the birth of both her children.
In affected members of a 3-generation family with hand-foot-genital syndrome (HFG; 140000), Debeer et al. (2002) identified a 27-bp in-frame duplication in the HOXA13 gene, resulting in expansion of the third of the HOXA13 protein's 3 N-terminal polyalanine tracts from 18 to 27 residues (9-alanine expansion). An affected member of this family married a member of another family in which mild synpolydactyly (186000) was caused by a missense mutation in the HOXD13 gene (142989.0007). The couple produced a girl heterozygous for both mutations who had digital abnormalities strikingly more severe than those in carriers of either individual mutation, indicating that the 2 mutations acted synergistically.
In a father and daughter with hand-foot-genital syndrome (HFG; 140000), Utsch et al. (2007) identified a heterozygous 42-bp duplication in the HOXA13 gene, resulting in the addition of 14 alanine residues into polyalanine tract III, which usually has 18 alanine residues. Transient cellular expression studies showed that the expanded protein formed cytoplasmic aggregates that sequestered both wildtype HOXA13 and wildtype HOXD13 (142989). The daughter had additional clinical features, including tethered spinal cord with neurogenic bladder and unilateral talipes equinovarus.
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Roux, M., Bouchard, M., Kmita, M. Multifaceted Hoxa13 function in urogenital development underlies the hand-foot-genital syndrome. Hum. Molec. Genet. 28: 1671-1681, 2019. [PubMed: 30649340] [Full Text: https://doi.org/10.1093/hmg/ddz013]
Sheth, R., Marcon, L., Bastida, M. F., Junco, M., Quintana, L., Dahn, R., Kmita M., Sharpe, J., Ros, M. A. Hox genes regulate digit patterning by controlling the wavelength of a Turing-type mechanism. Science 338: 1476-1480, 2012. [PubMed: 23239739] [Full Text: https://doi.org/10.1126/science.1226804]
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