Mutations in LRPAP1 Are Associated with Severe Myopia in Humans

Aldahmesh, Mohammed A.; Khan, Arif O.; Alkuraya, Hisham; Adly, Nouran; Anazi, Shamsa; Al-Saleh, Ahmed A.; Mohamed, Jawahir Y.; Hijazi, Hadia; Prabakaran, Sarita; Tacke, Marlene; Al-Khrashi, Abdullah; Hashem, Mais; Reinheckel, Thomas; Assiri, Abdullah M.; Alkuraya, Fowzan S.

doi:10.1016/j.ajhg.2013.06.002

Cited by 101 publications

(70 citation statements)

References 45 publications

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“…Population-based epidemiological investigations found that the disease is associated with environmental risk factors, such as a close reading distance and less outdoor activity (8,9). With the advent of nextgeneration sequencing, a few of disease genes have been discovered in recent years (18)(19)(20)(21)(22)(23)(24). Because myopia is dependent on both genetics and lifestyle and preschool children have less exposure to environmental risks, we designed this study using a special cohort with EOHM.…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…In these familial cases, linkage analysis has been performed. This approach has proven to be powerful for other familial forms of complex disease such as myopia 72 and systemic lupus erythematosus. 73 To date, 17 distinct potential loci for KC are described; 74 however, only three of these loci have been independently replicated, 5q21, 75,76 5q32 75,77 and 14q11.…”

Section: Geneticsmentioning

confidence: 99%

The pathogenesis of keratoconus

Davidson¹,

Hayes

Hardcastle³

et al. 2013

Eye

293

200

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Keratoconus (KC) is a common degenerative condition that frequently results in visual loss with an onset typically in early adulthood. It is the single most common reason for keratoplasty in the developed world. The cause and underlying pathological mechanism are unknown, but both environmental and genetic factors are thought to contribute to the development of the disease. Various strategies have been employed to address the gap in our understanding of this complex disease, with the expectation that over time more sophisticated therapies will be developed. In this review we summarise our current knowledge of the aetiology and risk factors associated with KC.

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“…These include Desbuquois dysplasia (MIM: 251450), CTSH-related syndrome (MIM: 116820), and LOXL3-related syndrome (MIM: 607163). [15][16][17] It is likely that GZF1-related myopia is similarly caused by abnormal modeling of the extracellular matrix, as evident by the severe myopia and retinal detachment. It will be of interest to test the contribution of milder variants in GZF1 to myopia in future studies.…”

mentioning

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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Mutations in LRPAP1 Are Associated with Severe Myopia in Humans

Cited by 101 publications

References 45 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

The pathogenesis of keratoconus

GZF1 Mutations Expand the Genetic Heterogeneity of Larsen Syndrome

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