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

TitleP4HA1 mutations cause a unique congenital disorder of connective tissue involving tendon, bone, muscle and the eye.
Publication TypeJournal Article
Year of Publication2017
AuthorsZou, Y, Donkervoort, S, Salo, AM, A Foley, R, Barnes, AM, Hu, Y, Makareeva, E, Leach, ME, Mohassel, P, Dastgir, J, Deardorff, MA, Cohn, RD, DiNonno, WO, Malfait, F, Lek, M, Leikin, S, Marini, JC, Myllyharju, J, Bönnemann, CG
JournalHum Mol Genet
Date Published2017 06 15
KeywordsAnimals, Basement Membrane, Bone and Bones, Child, Collagen Type IV, Connective Tissue, Humans, Male, Mice, Mice, Knockout, Muscles, Mutation, Osteochondrodysplasias, Procollagen-Proline Dioxygenase, Prolyl Hydroxylases, Tendons

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.

Alternate JournalHum. Mol. Genet.
PubMed ID28419360
PubMed Central IDPMC6075373
Grant ListUM1 HG008900 / HG / NHGRI NIH HHS / United States