P4HA1 mutations cause a unique congenital disorder of connective tissue involving tendon, bone, muscle and the eye

Abstract

Collagen prolyl 4-hydroxylases (C-P4Hs) play a central role in the formation and stabilization of the triple helical domain of collagens. P4HA1 encodes the catalytic α(I) subunit of the main C-P4H isoenzyme (C-P4H-I). We now report human bi-allelic P4HA1 mutations in a family with a congenital-onset disorder of connective tissue, manifesting as early-onset joint hypermobility, joint contractures, muscle weakness and bone dysplasia as well as high myopia, with evidence of clinical improvement of motor function over time in the surviving patient. Similar to P4ha1 null mice, which die prenatally, the muscle tissue from P1 and P2 was found to have reduced collagen IV immunoreactivity at the muscle basement membrane. Patients were compound heterozygous for frameshift and splice site mutations leading to reduced, but not absent, P4HA1 protein level and C-P4H activity in dermal fibroblasts compared to age-matched control samples. Differential scanning calorimetry revealed reduced thermal stability of collagen in patient-derived dermal fibroblasts versus age-matched control samples. Mutations affecting the family of C-P4Hs, and in particular C-P4H-I, should be considered in patients presenting with congenital connective tissue/myopathy overlap disorders with joint hypermobility, contractures, mild skeletal dysplasia and high myopia.

Prolyl and lysyl hydroxylases in collagen synthesis

“…Until now, only a single human patient with a connective tissue disease caused by P4HA1 mutations has been identified. [ 87] The disease manifests as early‐onset joint hypermobility, joint contractures, muscle weakness, bone dysplasia, high myopia and delayed motor milestones with improvement of motor function over time. The patient was found to be a compound heterozygote for frameshift and splice site mutations in the P4HA1 gene leading to reduced P4HA1 protein level, collagen P4H activity and thermal stability of collagen.…”

Role of prolyl hydroxylation in the molecular interactions of collagens

“…In humans, bi-allelic mutations in P4HA1 , the gene encoding the catalytic α(I) subunit of the C-P4H-I, have been shown to lead to a congenital connective tissue disorder with joint hypermobility, contractures, mild skeletal dysplasia and high myopia [18]. In gene-modified mice, the complete homozygous inactivation of the same gene leads to an 80% decrease in total C-P4H activity and embryonic death at E10.5 [19].…”

P4HA1 regulates human colorectal cancer cells through HIF1α‑mediated Wnt signaling

“…These findings may in part explain the present results, wherein silencing of P4HA1 downregulates cellular proliferation, reduced cancer stemness and decreased chemoresistance plausibly through the breakdown of the ECM. As has been demonstrated previously, it is likely that the silencing of P4HA1 decreases the turnover of collagen in the matrix (33). The absence of collagen abrogates activation of the focal adhesion kinase (FAK) through β1-integrin (34).…”