Autosomal‐dominant myopia associated to a novel P4HA2 missense variant and defective collagen hydroxylation

Abstract

We recently described a complex multisystem syndrome in which mild-moderate myopia segregated as an independent trait. A plethora of genes has been related to sporadic and familial myopia. More recently, in Chinese patients severe myopia (MYP25, OMIM:617238) has been linked to mutations in P4HA2 gene. Seven family members complaining of reduced distance vision especially at dusk underwent complete ophthalmological examination. Whole-exome sequencing was performed to identify the gene responsible for myopia in the pedigree. Moderate myopia was diagnosed in the family which was associated to the novel missense variant c.1147A > G p.(Lys383Glu) in the prolyl 4-hydroxylase,alpha-polypeptide 2 (P4HA2) gene, which catalyzes the formation of 4-hydroxyproline residues in the collagen strands. In vitro studies demonstrated P4HA2 mRNA and protein reduced expression level as well as decreased collagen hydroxylation and deposition in mutated fibroblast primary cultures compared to healthy cell lines. This study suggests that P4HA2 mutations may lead to myopic axial elongation of eyeball as a consequence of quantitative and structural alterations of collagen. This is the first confirmatory study which associates a novel dominant missense variant in P4HA2 with myopia in Caucasian patients. Further studies in larger cohorts are advisable to fully clarify genotype-phenotype correlations.

IMI – Myopia Genetics Report

“…WES has been conducted primarily in case-control studies of early-onset high myopia or in specific families with a particular phenotype (i.e., myopic anisometropia) or inheritance pattern (i.e., X-linked) 108–111. Several novel mutations in known myopia genes were identified this way: CCDC111 ,109 NDUFAF7 ,110 P4HA2 ,108 SCO2 ,112 UNC5D ,111 BSG ,113 ARR3 ,114 LOXL3 ,115 SLC39A5 ,116 LRPAP1 ,117 CTSH ,117 ZNF644 118,119. Although most genetic variants displayed an autosomal dominant hereditary pattern,108,112,118,119 X-linked heterozygous mutations were identified in ARR3 , only in female family members 114.…”

“…Several novel mutations in known myopia genes were identified this way: CCDC111 ,109 NDUFAF7 ,110 P4HA2 ,108 SCO2 ,112 UNC5D ,111 BSG ,113 ARR3 ,114 LOXL3 ,115 SLC39A5 ,116 LRPAP1 ,117 CTSH ,117 ZNF644 118,119. Although most genetic variants displayed an autosomal dominant hereditary pattern,108,112,118,119 X-linked heterozygous mutations were identified in ARR3 , only in female family members 114. The functions of these novel genes include DNA transcription ( CCDC111 , ZNF644 ), mitochondrial function ( NDUFAF7 , SCO2) , collagen synthesis ( P4HA2 ), cell signaling ( UNC5D , BSG ), retina-specific signal transduction ( ARR3 ), TGF-beta pathway ( LOXL3 , SLC39A5 , LRPAP1 ), and degradation of proteins in lysosomes ( CTSH ).…”

Prolyl and lysyl hydroxylases in collagen synthesis

“…P4HA2 mutations have been identified and associated with non-syndromic high myopia. [88,89] Heterozygous P4HB (PDI) mutations have been identified in Cole-Carpenter syndrome with bone fragility and other symptoms. [90][91][92]…”

The Genetics of Myopia

“…Studies employing WES to date have either focused on family designs (e.g. particular inheritance patterns such as X-linkage or conditions such as myopic anisometropia) or case-control studies of early onset high myopia [119][120][121][122]. The WES-based approaches identified several novel mutations in known myopia genes (Table 5.5).…”

“…ATL3 and AKAP12) [131]. In the family studies, most variants displayed an autosomal dominant mode of inheritance [119,123,124,130] although X-linked heterozygous mutations were found in ARR3 [126].…”