HOXD13 – Synpolydactyly Type 1

Synpolydactyly type 1 (SPD1) is an autosomal dominant limb malformation characterized by webbing of the third and fourth fingers and fusion or duplication of the fourth and fifth toes (PMID:31870337). Heterozygous polyalanine tract expansions in HOXD13, notably c.183_206dup (p.Ala64_Ala71dup), underlie SPD1 in multiple families with complete cosegregation (PMID:31870337). In a novel cohort of 98 affected individuals from 38 families, and a literature review encompassing 160 additional cases across 49 families, alanine repeat expansions were the predominant variant class (PMID:37427568). Other pathogenic alleles include splice donor site mutation c.781+1G>A (p.Gly190fsTer4) causing truncated protein loss of function (PMID:24055421). Functional modeling in mice harboring the 21-bp duplication (spdh) recapitulates human SPD1 phenotypes, demonstrating a gain-of-function/dominant-negative mechanism with impaired ossification (PMID:11543619, PMID:11850178). Cellular assays show mutant HOXD13 misfolding, cytoplasmic aggregation, and defective DNA binding in luciferase and ChIP studies (PMID:15333588, PMID:23995701). Global binding profile shifts of missense mutant p.Gln325Lys reveal altered target specificity, linking genotype to phenotypic severity (PMID:23995701). Together, genetic and experimental evidence definitively establish HOXD13 haploinsufficiency and polyalanine expansion-mediated toxicity as the molecular basis for SPD1. Key take-home: HOXD13 variant analysis enables precise SPD1 diagnosis and informs genetic counseling.

References

• BMC Medical Genetics • 2019 • A heterozygous duplication variant of the HOXD13 gene caused synpolydactyly type 1 with variable expressivity in a Chinese family. PMID:31870337
• Genetics in Medicine • 2023 • HOXD13-associated synpolydactyly: Extending and validating the genotypic and phenotypic spectrum with 38 new and 49 published families. PMID:37427568
• Developmental Biology • 2001 • The mouse Hoxd13(spdh) mutation, a polyalanine expansion similar to human type II synpolydactyly (SPD), disrupts the function but not the expression of other Hoxd genes. PMID:11543619
• Mechanisms of Development • 2002 • The synpolydactyly homolog (spdh) mutation in the mouse -- a defect in patterning and growth of limb cartilage elements. PMID:11850178
• Gene • 2013 • A splice donor site mutation in HOXD13 underlies synpolydactyly with cortical bone thinning. PMID:24055421
• Human Molecular Genetics • 2004 • A molecular pathogenesis for transcription factor associated poly-alanine tract expansions. PMID:15333588
• Genome Research • 2013 • Distinct global shifts in genomic binding profiles of limb malformation-associated HOXD13 mutations. PMID:23995701

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