Recessive Mutations in<i>LEPREL1</i>Underlie a Recognizable Lens Subluxation Phenotype

Khan, Arif O.; Aldahmesh, Mohammed A.; Alsharif, Hadeel; Alkuraya, Fowzan S.

doi:10.3109/13816810.2014.985847

Cited by 27 publications

(22 citation statements)

References 22 publications

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“…Mutations in this gene have been reported in patients with HM in western Asia (19,29) and China (30). Leprel1 knockout (KO) mice with abnormal collagen chemistry partially recapitulate the myopic changes (31).…”

Section: Significancementioning

confidence: 99%

Trio-based exome sequencing arrests de novo mutations in early-onset high myopia

Jin

Huang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The etiology of the highly myopic condition has been unclear for decades. We investigated the genetic contributions to early-onset high myopia (EOHM), which is defined as having a refraction of less than or equal to −6 diopters before the age of 6, when children are less likely to be exposed to high educational pressures. Trios (two nonmyopic parents and one child) were examined to uncover pathogenic mutations using whole-exome sequencing. We identified parent-transmitted biallelic mutations or de novo mutations in asyet-unknown or reported genes in 16 probands. Interestingly, an increased rate of de novo mutations was identified in the EOHM patients. Among the newly identified candidate genes, a BSG mutation was identified in one EOHM proband. Expanded screening of 1,040 patients found an additional four mutations in the same gene. Then, we generated Bsg mutant mice to further elucidate the functional impact of this gene and observed typical myopic phenotypes, including an elongated axial length. Using a trio-based exonic screening study in EOHM, we deciphered a prominent role for de novo mutations in EOHM patients without myopic parents. The discovery of a disease gene, BSG, provides insights into myopic development and its etiology, which expands our current understanding of high myopia and might be useful for future treatment and prevention.early-onset high myopia | de novo mutations | BSG | rare inherited mutations

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Section: Significancementioning

confidence: 99%

Trio-based exome sequencing arrests de novo mutations in early-onset high myopia

Jin

Huang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Human mutations in P3H2 (Leprel1) have been shown to cause the eye disorder high myopia (13)(14)(15). Two different P3H2 knock-out mice have so far been generated by separate laboratories, the first was embryonic lethal (16), whereas the second had no obvious phenotype (17).…”

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confidence: 99%

P3h3-null and Sc65-null Mice Phenocopy the Collagen Lysine Under-hydroxylation and Cross-linking Abnormality of Ehlers-Danlos Syndrome Type VIA

Hudson

Weis

Rai

et al. 2017

Journal of Biological Chemistry

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Edited by Xiao-Fan WangTandem mass spectrometry was applied to tissues from targeted mutant mouse models to explore the collagen substrate specificities of individual members of the prolyl 3-hydroxylase (P3H) gene family. Previous studies revealed that P3h1 preferentially 3-hydroxylates proline at a single site in collagen type I chains, whereas P3h2 is responsible for 3-hydroxylating multiple proline sites in collagen types I, II, IV, and V. In screening for collagen substrate sites for the remaining members of the vertebrate P3H family, P3h3 and Sc65 knock-out mice revealed a common lysine under-hydroxylation effect at helical domain cross-linking sites in skin, bone, tendon, aorta, and cornea. No effect on prolyl 3-hydroxylation was evident on screening the spectrum of known 3-hydroxyproline sites from all major tissue collagen types. However, collagen type I extracted from both The collagen family of proteins has evolved into many different genes and gene translational products each with variably regulated post-translational modifications (1, 2). Even within a single genetic type of collagen, the post-translational quality of the protein is known to be regulated with a high degree of tissue specificity (3, 4). The functional significance of this post-translational variability is still not fully understood, although for fibril-forming collagens the number, placement, and chemistry of covalent intermolecular cross-links seem to be critically important regulators of tissue material properties and function (5-7).In the last decade, new insights on the significance of a relatively rare collagen modification, prolyl 3-hydroxylation, came from the discovery that recessive forms of osteogenesis imperfecta (OI) 2 are caused by biallelic mutations in prolyl 3-hydroxylase 1 (P3H1; Lepre1), CRTAP (Leprel3), or CypB (PPIB) (8). These proteins, which form a P3H1 enzyme complex, act on nascent collagen chains in the ER (9). Mutations in at least 6 further genes that encode either enzymes (e.g. PLOD2 encoding lysyl hydroxylase-2 (LH2) (10)) or chaperones (e.g. FKBP10 encoding FKBP65 (11, 12)), needed for collagen modification, folding, transport, and normal mineralization, have been shown to cause OI variants. We have gained insights on the disease-causing mechanisms by analyzing tissue collagens from OI patients and mouse models of OI. For example, P3H1, CRTAP, and PPIB mutations all cause telopeptide lysine overhydroxylation (5), whereas PLOD2 or FKBP10 mutations cause telopeptide lysine under-hydroxylation (10 -12). A common effect from all these mutations is an altered collagen cross-linking chemistry. These findings suggest an interplay in the ER between the prolyl 3-hydroxylation complex and the lysyl hydroxylation machinery.Human mutations in P3H2 (Leprel1) have been shown to cause the eye disorder high myopia (13-15). Two different P3H2 knock-out mice have so far been generated by separate laboratories, the first was embryonic lethal (16), whereas the second had no obvious phenotype (17). Mass spectral analysis of...

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“…P3H2 is known to be mutated in a Mendelian form of severe myopia with an elongated axis of the globe, a phenotype that strongly resembles that observed in the affected individuals described in this study. 13 Thus, although we cannot rule out the indirect involvement of other genes in the pathogenesis of GZF1-related Larsen syndrome, it seems plausible that at least the eye phenotype is in part related to dysregulation of P3H2. It is remarkable that although the eye phenotype is highly similar between the two families, the articular phenotypic severity is variable.…”

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confidence: 99%

GZF1 Mutations Expand the Genetic Heterogeneity of Larsen Syndrome

Patel

Shamseldin

Sakati

et al. 2017

The American Journal of Human Genetics

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Larsen syndrome is characterized by the dislocation of large joints and other less consistent clinical findings. Heterozygous FLNB mutations account for the majority of Larsen syndrome cases, but biallelic mutations in CHST3 and B4GALT7 have been more recently described, thus confirming the existence of recessive forms of the disease. In a multiplex consanguineous Saudi family affected by severe and recurrent large joint dislocation and severe myopia, we identified a homozygous truncating variant in GZF1 through a combined autozygome and exome approach. Independently, the same approach identified a second homozygous truncating GZF1 variant in another multiplex consanguineous family affected by severe myopia, retinal detachment, and milder skeletal involvement. GZF1 encodes GDNF-inducible zinc finger protein 1, a transcription factor of unknown developmental function, which we found to be expressed in the eyes and limbs of developing mice. Global transcriptional profiling of cells from affected individuals revealed a shared pattern of gene dysregulation and significant enrichment of genes encoding matrix proteins, including P3H2, which hints at a potential disease mechanism. Our results suggest that GZF1 mutations cause a phenotype of severe myopia and significant articular involvement not previously described in Larsen syndrome.

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Recessive Mutations inLEPREL1Underlie a Recognizable Lens Subluxation Phenotype

Cited by 27 publications

References 22 publications

Trio-based exome sequencing arrests de novo mutations in early-onset high myopia

Trio-based exome sequencing arrests de novo mutations in early-onset high myopia

P3h3-null and Sc65-null Mice Phenocopy the Collagen Lysine Under-hydroxylation and Cross-linking Abnormality of Ehlers-Danlos Syndrome Type VIA

GZF1 Mutations Expand the Genetic Heterogeneity of Larsen Syndrome

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