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1.
Clin Genet ; 93(5): 982-991, 2018 05.
Article in English | MEDLINE | ID: mdl-29364500

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.


Subject(s)
Collagen/genetics , Hydroxylation/genetics , Myopia/genetics , Prolyl Hydroxylases/genetics , Adolescent , Adult , Child , China/epidemiology , Collagen/metabolism , Exome/genetics , Female , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Mutation, Missense/genetics , Myopia/epidemiology , Myopia/pathology , Pedigree , Phenotype , Young Adult
2.
Mol Neurobiol ; 45(3): 596-604, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22648535

ABSTRACT

Phospholipases (PLA2s) are a superfamily of enzymes characterized by the ability to specifically hydrolyze the sn-2 ester bond of phospholipids generating arachidonic acid, utilized in inflammatory responses, and lysophospholipids involved in the control of cell membrane remodeling and fluidity. PLA2s have been so far considered a crucial element in the etiopathogenesis of several neurological diseases such as cerebral ischemia, multiple sclerosis, Parkinson's disease, and Alzheimer's disease (AD). In AD, the role of beta-amyloid (Aß) fragments is well established although still more elusive are the molecular events of the cascade that from the Aß accumulation leads to neurodegeneration with its clinical manifestations. However, it is well known that inflammation and alteration of lipid metabolism are common features of AD brains. Findings obtained from in vitro studies, animal models, and human brain imaging analysis point towards cPLA2 as a key molecule in the onset and maintenance of the neurodegenerative mechanism(s) of AD. In this review, we have focused on the molecular and biological evidence of the involvement of cPLA2s in the pathogenesis of AD. An insight into the molecular mechanism(s) underlying the action and the regulation of cPLA2 is of tremendous interest in the pharmaceutical and biotechnology industry in developing selective and potent inhibitors able to modulate the onset and/or the outcome of AD.


Subject(s)
Alzheimer Disease/enzymology , Alzheimer Disease/etiology , Calcium/metabolism , Phospholipases A2, Cytosolic/metabolism , Alzheimer Disease/pathology , Alzheimer Disease/therapy , Animals , Central Nervous System/enzymology , Central Nervous System/pathology , Humans , Models, Biological , Molecular Targeted Therapy , Phospholipases A2, Cytosolic/antagonists & inhibitors
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