Next generation sequencing‐based molecular diagnosis in familial congenital cataract expands the mutational spectrum in known congenital cataract genes

Astiazarán, Mirena C; García-Montaño, Leopoldo A; Sánchez-Moreno, F. M.; Matiz-Moreno, Humberto; Ruíz, Juan-Carlos

doi:10.1002/ajmg.a.40524

Cited by 26 publications

(17 citation statements)

References 42 publications

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“…This ‘notochord development’ gene-set consists in 18 genes, including EPHA2 , EFNA1 , and NOTO . EPHA2 encodes the EPH receptor A2, and mutations in this gene are the cause of certain genetically-related cataract disorders, including congenital cataract and age-related cataract 47 – 51 . EFNA1 encodes the ephrin A1 which has been implicated in mediating developmental events 52 and in apoptosis and retinal epithelial development 53 .…”

Section: Resultsmentioning

confidence: 99%

A large multiethnic GWAS meta-analysis of cataract identifies new risk loci and sex-specific effects

Choquet

Melles²,

Anand

et al. 2021

Nat Commun

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Cataract is the leading cause of blindness among the elderly worldwide and cataract surgery is one of the most common operations performed in the United States. As the genetic etiology of cataract formation remains unclear, we conducted a multiethnic genome-wide association meta-analysis, combining results from the GERA and UK Biobank cohorts, and tested for replication in the 23andMe research cohort. We report 54 genome-wide significant loci, 37 of which were novel. Sex-stratified analyses identified CASP7 as an additional novel locus specific to women. We show that genes within or near 80% of the cataract-associated loci are significantly expressed and/or enriched-expressed in the mouse lens across various spatiotemporal stages as per iSyTE analysis. Furthermore, iSyTE shows 32 candidate genes in the associated loci have altered gene expression in 9 different gene perturbation mouse models of lens defects/cataract, suggesting their relevance to lens biology. Our work provides further insight into the complex genetic architecture of cataract susceptibility.

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Section: Resultsmentioning

confidence: 99%

A large multiethnic GWAS meta-analysis of cataract identifies new risk loci and sex-specific effects

Choquet

Melles²,

Anand

et al. 2021

Nat Commun

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“…The CRYβB2 protein is an abundant ocular lens protein, and mutations have been associated with congenital cataracts and macular degeneration [19, 20]. Mouse model studies have also demonstrated Crybb2 −/− mice have reduced fertility compared with wild-type mice via reduced expression of cell cycle and survival genes [21, 22].…”

Section: Introductionmentioning

confidence: 99%

A functional role for the cancer disparity-linked genes, CRYβB2 and CRYβB2P1, in the promotion of breast cancer

et al. 2019

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Background In the USA, the breast cancer mortality rate is 41% higher for African-American women than non-Hispanic White women. While numerous gene expression studies have classified biological features that vary by race and may contribute to poorer outcomes, few studies have experimentally tested these associations. CRYβB2 gene expression has drawn particular interest because of its association with overall survival and African-American ethnicity in multiple cancers. Several reports indicate that overexpression of the CRYβB2 pseudogene, CRYβB2P1, and not CRYβB2 is linked with race and poor outcome. It remains unclear whether either or both genes are linked to breast cancer outcomes. This study investigates CRYβB2 and CRYβB2P1 expression in human breast cancers and breast cancer cell line models, with the goal of elucidating the mechanistic contribution of CRYβB2 and CRYβB2P1 to racial disparities. Methods Custom scripts for CRYβB2 or CRYβB2P1 were generated and used to identify reads that uniquely aligned to either gene. Gene expression according to race and tumor subtype were assessed using all available TCGA breast cancer RNA sequencing alignment samples (n = 1221). In addition, triple-negative breast cancer models engineered to have each gene overexpressed or knocked out were developed and evaluated by in vitro, biochemical, and in vivo assays to identify biological functions. Results We provide evidence that CRYβB2P1 is expressed at higher levels in breast tumors compared to CRYβB2, but only CRYβB2P1 is significantly increased in African-American tumors relative to White American tumors. We show that independent of CRYβB2, CRYβB2P1 enhances tumorigenesis in vivo via promoting cell proliferation. Our data also reveal that CRYβB2P1 may function as a non-coding RNA to regulate CRYβB2 expression. A key observation is that the combined overexpression of both genes was found to suppress cell growth. CRYβB2 overexpression in triple-negative breast cancers increases invasive cellular behaviors, tumor growth, IL6 production, immune cell chemoattraction, and the expression of metastasis-associated genes. These data underscore that both CRYβB2 and CRYβB2P1 promote tumor growth, but their mechanisms for tumor promotion are likely distinct. Conclusions Our findings provide novel data emphasizing the need to distinguish and study the biological effects of both CRYβB2 and CRYβB2P1 as both genes independently promote tumor progression. Our data demonstrate novel molecular mechanisms of two understudied, disparity-linked molecules.

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“…Furthermore, congenital cataract is a genetically heterogeneous disease [25]. Next-generation DNA sequencing (NGS) technologies have been validated to determine the precise genetic cause of bilateral congenital cataracts in about 75% of individuals but JAM3 is not usually included in these panels [26,27]. Our results contribute to expand the mutational spectrum of genes causing congenital cataract, in approaching the prenatal diagnosis.…”

Section: Discussionmentioning

confidence: 87%

A novel homozygous variant in JAM3 gene causing hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts (HDBSCC) with neonatal onset

et al. 2021

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Background JAM3 gene, located on human chromosome 11q25, encodes a member of the junctional adhesion molecule (JAM) family. Mutations of this gene are associated with hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts (HDBSCC). Case report Herein, we present a newborn male with a prenatal suspicion of bilateral cataracts but without fetal ultrasound findings of cortical malformations. He was postnatally diagnosed with a clinical picture of HDBSCC and Early-onset Developmental and Epileptic Encephalopathy (DEE), associated to a homozygous variant of JAM3 gene. Conclusion Identification of this variant in affected individuals has implications for perinatal and postnatal management and genetic counseling. To the best of our knowledge, this is the first case reported of a child with a JAM3 variant in Italy, from a different ethnic background than the other reported children until now (Saudi Arabian, Turkish, Afghani, and Moroccan origin). JAM3 screening could be requested in prenatal diagnosis of fetal congenital cataracts and included in Next-Generation DNA Sequencing panels.

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Next generation sequencing‐based molecular diagnosis in familial congenital cataract expands the mutational spectrum in known congenital cataract genes

Cited by 26 publications

References 42 publications

A large multiethnic GWAS meta-analysis of cataract identifies new risk loci and sex-specific effects

A large multiethnic GWAS meta-analysis of cataract identifies new risk loci and sex-specific effects

A functional role for the cancer disparity-linked genes, CRYβB2 and CRYβB2P1, in the promotion of breast cancer

A novel homozygous variant in JAM3 gene causing hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts (HDBSCC) with neonatal onset

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