Appraisal of prolyl 4-hydroxylase alpha subunit gene polymorphisms in Spondyloepimetaphyseal dysplasia of Handigodu type (SEMDHG)

Abstract

Background

The Handigodu variant of Spondyloepimetaphyseal Dysplasia (SEMD_HG) is a severe, progressive osteoarthritic disorder characterized by chronic pain and joint degeneration. Clinically, the disorder presents in three distinct phenotypic forms, each exhibiting varying degrees of stature reduction and disease severity. Urine analysis of affected individuals reveals an elevated peptide-bound proline to 4-hydroxyproline ratio relative to controls, suggesting disruptions in collagen metabolism. Given the critical role of prolyl 4-hydroxylase enzymes in stabilizing collagen structure, this study undertook a comprehensive sequence analysis of all three isoforms of prolyl 4-hydroxylase in both affected and unaffected individuals to elucidate potential molecular underpinnings of the disorder.

Method

The entire exonic regions and 2000 base pairs upstream of the translation start sites of the P4HA1, P4HA2, and P4HA3 genes were sequenced in a cohort of 300 individuals, comprising 166 affected and 134 unaffected individuals.

Results

Sequence analysis of the α (I), α (II), and α (III) subunit genes identified three novel SNPs and a 39-bp deletion variant, in addition to ten previously reported SNPs catalogued in dbSNP. The SNP rs28384495 in P4HA1, the 39-bp deletion variant, and a novel mutation (SNP3) in P4HA3 exhibited significantly different allele frequencies between patients and controls. Genotype association analysis revealed that SNPs in P4HA1 and P4HA3 were associated with Type 2 and Type 3 HD under various genetic models. Notably, all Type 2 HD patients were heterozygous for the 39-bp deletion, whereas all Type 3 HD patients were homozygous for the variant. Haplotype analysis corroborated the findings of the genotype association analysis.

Conclusion

This study is the first to account an association between the P4H gene and disease. Further research is needed to evaluate the functional implications of the identified mutations.