title: Post-translationally abnormal collagens of prolyl 3-hydroxylase-2 null mice offer a pathobiological mechanism for the high myopia linked to human LEPREL1 mutations.
abstract: Myopia, the leading cause of visual impairment worldwide, results from an increase in the axial length of the eyeball. Mutations in LEPREL1, the gene encoding prolyl 3-hydroxylase-2 (P3H2), have recently been identified in individuals with recessively inherited nonsyndromic severe myopia. P3H2 is a member of a family of genes that includes three isoenzymes of prolyl 3-hydroxylase (P3H), P3H1, P3H2, and P3H3. Fundamentally, it is understood that P3H1 is responsible for converting proline to 3-hydroxyproline. This limited additional knowledge also suggests that each isoenzyme has evolved different collagen sequence-preferred substrate specificities. In this study, differences in prolyl 3-hydroxylation were screened in eye tissues from P3h2-null (P3h2(n/n)) and wild-type mice to seek tissue-specific effects due the lack of P3H2 activity on post-translational collagen chemistry that could explain myopia. The mice were viable and had no gross musculoskeletal phenotypes. Tissues from sclera and cornea (type I collagen) and lens capsule (type IV collagen) were dissected from mouse eyes, and multiple sites of prolyl 3-hydroxylation were identified by mass spectrometry. The level of prolyl 3-hydroxylation at multiple substrate sites from type I collagen chains was high in sclera, similar to tendon. Almost every known site of prolyl 3-hydroxylation in types I and IV collagen from P3h2(n/n) mouse eye tissues was significantly under-hydroxylated compared with their wild-type littermates. We conclude that altered collagen prolyl 3-hydroxylation is caused by loss of P3H2. We hypothesize that this leads to structural abnormalities in multiple eye tissues, but particularly sclera, causing progressive myopia.
authors: From the Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, Washington 98195 and.
authors: David M
authors: DM
authors: Hudson
authors: the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030.
authors: Kyu Sang
authors: KS
authors: Joeng
authors: From the Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, Washington 98195 and.
authors: Rachel
authors: R
authors: Werther
authors: the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030.
authors: Abbhirami
authors: A
authors: Rajagopal
authors: From the Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, Washington 98195 and.
authors: MaryAnn
authors: M
authors: Weis
authors: the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030.
authors: Brendan H
authors: BH
authors: Lee
authors: From the Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, Washington 98195 and deyre@u.washington.edu.
authors: David R
authors: DR
authors: Eyre
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D024042:Collagen Type I / Q000378:metabolism; D024141:Collagen Type IV / Q000378:metabolism; D003315:Cornea / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D006900:Hydroxylation; D007903:Lens Capsule, Crystalline / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D009216:Myopia / Q000235:genetics*; D009928:Organ Specificity; D010641:Phenotype; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics* / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012590:Sclera / Q000201:enzymology / Q000473:pathology
chemical_list: D024042:Collagen Type I; D024141:Collagen Type IV; D011393:Procollagen-Proline Dioxygenase; C586944:LEPREL1 protein, mouse; C568061:P3H2 protein, human
keywords: 3-Hydroxyproline; Animal Model; Collagen; Extracellular Matrix; Mass Spectrometry (MS); Post-translational Modification (PTM); Prolyl 3-Hydroxylase; Sclera
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