P4HA2 – Myopia

Prolyl 4-hydroxylase subunit alpha-2, encoded by P4HA2, catalyzes formation of 4-hydroxyproline residues in collagen strands. Myopia (MONDO:0001384) is a refractive error with axial elongation of the eye. Recent studies have implicated heterozygous P4HA2 variants in autosomal-dominant nonsyndromic high myopia, supported by segregation and functional assays.

Two independent pedigrees and additional sporadic cases yielded six unrelated probands with heterozygous P4HA2 variants. A novel missense variant, c.1147A>G (p.Lys383Glu), was identified in a Caucasian family of seven affected individuals, segregating with moderate myopia (PMID:29364500). In a Chinese family, c.871G>A (p.Glu291Lys) co-segregated with high myopia (PMID:25741866). Screening 186 additional cases uncovered four more variants in five cases, including two protein-truncating alleles and two deleterious missense changes (PMID:25741866). Segregation was observed in two multi-generation families encompassing eight additional affected relatives (PMID:25741866).

The variant spectrum consists predominantly of missense substitutions—c.1147A>G (p.Lys383Glu), c.871G>A (p.Glu291Lys), c.419A>G (p.Gln140Arg), c.448A>G (p.Ile150Val)—and protein-truncating alleles, including c.1327A>G (p.Lys443Ter) and c.1352_1353del (p.Val451GlyfsTer9) (PMID:25741866). These variants are absent or extremely rare in population databases.

In vitro functional assays demonstrate that fibroblasts from individuals with p.Lys383Glu exhibit reduced P4HA2 mRNA and protein levels, with decreased collagen hydroxylation and deposition compared to controls (PMID:29364500). The p.Glu291Lys substitution leads to unstable mRNA with premature degradation, impairing posttranslational modification of collagen (PMID:25741866).

The pathogenic mechanism likely involves haploinsufficiency or quantitative reduction of collagen hydroxylation in the sclera, promoting extracellular matrix derangement and axial elongation of the globe. These molecular findings align with the high myopia phenotype in patients (PMID:29364500; PMID:25741866).

No conflicting evidence has been reported to date. Larger cohort studies are warranted to refine genotype–phenotype correlations and assess variant penetrance.

Key Take-home: Heterozygous P4HA2 variants meet moderate clinical validity for autosomal-dominant myopia, supporting their inclusion in genetic testing panels and informing diagnostic decision-making.

References

• Clinical Genetics • 2018 • Autosomal-dominant myopia associated to a novel P4HA2 missense variant and defective collagen hydroxylation. PMID:29364500
• Genetics in Medicine • 2015 • Mutations of P4HA2 encoding prolyl 4-hydroxylase 2 are associated with nonsyndromic high myopia. PMID:25741866

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