Identification of OSBPL2 as a novel candidate gene for progressive nonsyndromic hearing loss by whole-exome sequencing

Xing, Guangqian; Yao, Jun; Wu, Bin; Liu, Tingting; Wei, Qinjun; Liu, Cheng; Lu, Yajie; Chen, Zhibin; Zheng, Heng; Yang, Xiaonan; Cao, Xin

doi:10.1038/gim.2014.90

Cited by 53 publications

(35 citation statements)

References 40 publications

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“…DIAPH1 interacts with the protein implicated in ADNSHL type DFNA67, OSBPL2 (36,37). Although DIAPH1 and OSBPL2 may thus be functionally related, repeated platelet counts in the index patient (IV:10) of the DFNA67 family reported by us earlier were normal.…”

Section: Discussionmentioning

confidence: 61%

Extension of the clinical and molecular phenotype of DIAPH1‐associated autosomal dominant hearing loss (DFNA1)

Neuhaus¹,

Lang‐Roth

Zimmermann

et al. 2016

Clinical Genetics

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In about 20% of non-syndromic hearing loss (NSHL) cases, inheritance is autosomal dominant (ADNSHL). DIAPH1 mutations define the ADNSHL locus DFNA1. We identified two new families with heterozygous truncating DIAPH1 mutations (p.Ala1210Serfs*31 and p.Arg1213*). In contrast to the extensively studied original DFNA1 family, hearing loss was not confined to low frequencies, but congenital manifestation and rapid progression were confirmed. In line with a recent unrelated study, we identified an association with thrombocytopenia, reclassifying DFNA1 as a syndrome. Consequently, we suggest to include the blood count into the initial clinical workup of patients with autosomal dominant hearing loss to guide the genetic diagnosis. We provide the first data on DIAPH1 expression in the organ of Corti, where it localizes to the inner pillar cells, at the base of the outer hair cells. Homozygous truncating DIAPH1 mutations located N-terminally to the DFNA1 mutations have recently been identified in autosomal recessive microcephaly. It is therefore noteworthy that we found DIAPH1 expression also in spiral ganglion neurons and in the barrier between the myelinating glia of the peripheral nervous system and oligodendrocytes that form the myelinating glia of the central nervous system (CNS).

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Section: Discussionmentioning

confidence: 61%

Extension of the clinical and molecular phenotype of DIAPH1‐associated autosomal dominant hearing loss (DFNA1)

Neuhaus¹,

Lang‐Roth

Zimmermann

et al. 2016

Clinical Genetics

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“…Besides the above observations linking ORP2 function to cellular lipid homeostasis and synthesis of steroid hormones, the protein was found to localize to the stereocilia of cochlear inner and outer hair cells. Heterozygous mutations in the OSBPL2 gene encoding ORP2 were reported to cause an autosomal dominant nonsyndromic hearing loss (11,12).…”

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confidence: 99%

Analysis of ORP2‐knockout hepatocytes uncovers a novel function in actin cytoskeletal regulation

et al. 2018

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ORP2 is implicated in cholesterol transport, triglyceride metabolism, and adrenocortical steroid hormone production. We addressed ORP2 function in hepatocytes by generating ORP2-knockout (KO) HuH7 cells by CRISPR-Cas9 gene editing, followed by analyses of transcriptome, F-actin morphology, migration, adhesion, and proliferation. RNA sequencing of ORP2-KO cells revealed >2-fold changes in 579 mRNAs. The Ingenuity Pathway Analysis (IPA) uncovered alterations in the following functional categories: cellular movement, cell-cell signaling and interaction, cellular development, cellular function and maintenance, cellular growth and proliferation, and cell morphology. Many pathways in these categories involved actin cytoskeleton, cell migration, adhesion, or proliferation. Analysis of the ORP2 interactome uncovered 109 putative new partners. Their IPA analysis revealed Ras homolog A (RhoA) signaling as the most significant pathway. Interactions of ORP2 with SEPT9, MLC12, and ARHGAP12 were validated by independent assays. ORP2-KO resulted in abnormal F-actin morphology characterized by impaired capacity to form lamellipodia, migration defect, and impaired adhesion and proliferation. Rescue of the migration phenotype and generation of typical cell surface morphology required an intact ORP2 phosphoinositide binding site, suggesting that ORP2 function involves phosphoinositide binding and transport. The results point at a novel function of ORP2 as a lipid-sensing regulator of the actin cytoskeleton, with impacts on hepatocellular migration, adhesion, and proliferation.-Kentala, H., Koponen, A., Kivelä, A. M., Andrews, R., Li, C., Zhou, Y., Olkkonen, V. M. Analysis of ORP2-knockout hepatocytes uncovers a novel function in actin cytoskeletal regulation.

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“…Hearing loss is a common sensorial disorder, with an incidence of 1 in 500–1000 among children1. At least half of these cases are attributable to genetic factors, and more than two-third of the cases in this subset are classified as non-syndromic hearing loss (NSHL)2, which is associated with autosomal dominant (AD) and recessive (AR), X-linked, and maternal inheritance patterns.…”

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confidence: 99%

Genetic Predisposition to Sporadic Congenital Hearing Loss in a Pediatric Population

Jung

Lee

Cho

et al. 2017

Sci Rep

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Discriminating between inherited and non-inherited sporadic hearing loss is challenging. Here, we attempted to delineate genetic inheritance in simplex cases of severe-to-profound congenital hearing loss in Korean children. Variations in SLC26A4 and GJB2 in 28 children with bilateral severe-to-profound non-syndromic hearing loss (NSHL) without familial history were analyzed using Sanger sequencing. Genetic analysis of individuals without mutations in SLC26A4 and GJB2 was performed by whole exome sequencing (WES). Bi-allelic mutations in SLC26A4 and GJB2 were identified in 12 and 3 subjects, respectively. Of the 13 individuals without mutations in SLC26A4 and GJB2, 2 and 1 carried compound heterozygous mutations in MYO15A and CDH23, respectively. Thus, 64.3% (18/28) of individuals with NSHL were determined to be genetically predisposed. Individuals with sporadic severe-to-profound NSHL were found to mostly exhibit an autosomal recessive inheritance pattern. Novel causative candidate genes for NSHL were identified by analysis of WES data of 10 families without mutations in known causative genes. Bi-allelic mutations predisposing to NSHL were identified in 64.3% of subjects with sporadic severe-to-profound NSHL. Given that several causative genes for NSHL are still unidentified, genetic inheritance of sporadic congenital hearing loss could be more common than that indicated by our results.

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Identification of OSBPL2 as a novel candidate gene for progressive nonsyndromic hearing loss by whole-exome sequencing

Cited by 53 publications

References 40 publications

Extension of the clinical and molecular phenotype of DIAPH1‐associated autosomal dominant hearing loss (DFNA1)

Extension of the clinical and molecular phenotype of DIAPH1‐associated autosomal dominant hearing loss (DFNA1)

Analysis of ORP2‐knockout hepatocytes uncovers a novel function in actin cytoskeletal regulation

Genetic Predisposition to Sporadic Congenital Hearing Loss in a Pediatric Population

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