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OXYSTEROL-BINDING PROTEIN-LIKE PROTEIN 2; OSBPL2

OXYSTEROL-BINDING PROTEIN-LIKE PROTEIN 2; OSBPL2

Alternative titles; symbolsOSBP-RELATED PROTEIN 2; ORP2KIAA0772HGNC Approved Gene Symbol: OSBPL2Cytogenetic location: 20q13.33 Genomic coordinates (GRCh38): ...

Alternative titles; symbols

  • OSBP-RELATED PROTEIN 2; ORP2
  • KIAA0772

HGNC Approved Gene Symbol: OSBPL2

Cytogenetic location: 20q13.33 Genomic coordinates (GRCh38): 20:62,238,520-62,296,182 (from NCBI)

▼ Description
OSBPL2 is a member of the OSBP family of intracellular lipid receptors. For background information on OSBPs, see OSBP2 (606729).

▼ Cloning and Expression
By screening for cDNAs with the potential to encode large proteins expressed in brain, Nagase et al. (1998) identified a cDNA encoding OSBPL2, which they called KIAA0772. KIAA0772 encodes a deduced 468-amino acid protein. RT-PCR analysis detected wide but moderate expression of KIAA0772, with low levels in skeletal muscle and lung.

By EST database searching for sequences homologous to OSBP (167040), followed by RT-PCR, Laitinen et al. (1999) identified 6 OSBP-related proteins, including OSBPL2, which they called ORP2. Northern blot analysis revealed wide expression of major 4.4- and 2.8-kb transcripts that were most abundant in brain, heart, kidney, liver, and placenta. In skeletal and cardiac muscle, 6.6- and 1.2-kb transcripts were detected, and in brain, a minor 6.0-kb transcript was detected.

Xu et al. (2001) cloned ORP2 by database searching and multiple rounds of cDNA library screening. ORP2 encodes a deduced 468-amino acid protein. Fluorescence microscopy demonstrated expression of ORP2 in Golgi, with brefeldin A treatment causing its relocation.

Lehto et al. (2001) used RT-PCR analysis with specific primers to isolate a full-length cDNA encoding ORP2. Sequence analysis predicted that the 480-amino acid protein contains a C-terminal sterol-binding (SB) domain of approximately 400 amino acids that includes the OSBP motif (EQVSHHPP). ORP2 has no N-terminal pleckstrin homology (PH) domain. It is most homologous to OSBPL1B (606730), with 85% identity in their SB domains.

Jaworski et al. (2001) cloned multiple OSBPs, including OSBPL2. RT-PCR analysis detected ubiquitous expression of OSBPL2, with highest levels in retina, retinal pigment epithelium choroid, pineal gland, and cultured retinal pigment epithelial cells.

Using RT-PCR, Xing et al. (2015) found that Osbpl2 was strongly expressed in mouse cochlea and brain and was also expressed in the heart, liver, spleen, lung, kidney, and muscle. By immunohistochemical analysis, they found that Osbpl2 was localized to the stria vascularis, spiral ganglion, spiral ligament, inner hair cells, and outer hair cells of mouse cochlea. By immunohistochemical analysis, Thoenes et al. (2015) found that Osbpl2 was prominently expressed in stereocilia of cochlear outer and inner hair cells of P20 and 6-month-old mice.

▼ Gene Function
Using yeast complementation assays, Xu et al. (2001) showed that ORP2 overexpression causes cessation of cell growth. Binding analysis showed strongest binding of ORP2 to phosphatidic acid, with weaker binding to cardiolipin and phosphatidylinositol 3-phosphate.

▼ Gene Structure
By sequence analysis, Lehto et al. (2001) determined that the OSBPL2 gene contains 14 exons. Jaworski et al. (2001) found that it contains 15 exons.

▼ Mapping
By sequence analysis, Lehto et al. (2001) mapped the OSBPL2 gene to chromosome 20. Jaworski et al. (2001) confirmed the localization on chromosome 20q.

▼ Molecular Genetics
Xing et al. (2015) studied a large, 7-generation Han Chinese family (JSNY-028) segregating autosomal dominant nonsyndromic hearing loss (DFNA67; 616340) in which mutations in known DFNA genes had been excluded. By whole-exome sequencing in 25 affected members of the family, they identified heterozygosity for a 2-bp deletion (c.153_154delCT; 606731.0001) corresponding to codons 51/52 in exon 3 of the OSBPL2 gene. They also studied 26 unaffected members of the family and found that the mutation segregated completely with the disorder. The mutation was filtered against the dbSNP (build 135), 1000 Genomes Project, HapMap, and YanHuang databases. Xing et al. (2015) then screened 452 sporadic patients and 38 probands from unrelated autosomal dominant nonsyndromic deafness pedigrees and identified a missense variant (c.583C-A; L195M) in exon 7 of the OSBPL2 gene. This mutation was not found in 300 controls; however, no family members were available for segregation analysis.

Using genomewide linkage analysis and whole-exome sequencing in a German family segregating autosomal dominant sensorineural hearing loss, Thoenes et al. (2015) identified a heterozygous 2-bp deletion (c.141_142delTG; 606731.0002) in the OSBPL2 gene. The mutation, which segregated with the phenotype, was not found in the 1000 Genomes Project (build 20110521) or the Exome Variant Server (ESP6500) databases.

▼ History
By radiation hybrid analysis, Nagase et al. (1998) mapped the OSBPL2 gene to chromosome 9.

▼ ALLELIC VARIANTS ( 2 Selected Examples):

.0001 DEAFNESS, AUTOSOMAL DOMINANT 67
OSBPL2, 2-BP DEL, 153CT
By whole-exome sequencing in affected members of a 7-generation Han Chinese family (JSNY-028) with nonsyndromic hearing loss (DFNA67; 616340), Xing et al. (2015) identified a heterozygous 2-bp deletion (c.153_154delCT, NM_144498.2) in exon 3 of the OSBPL2 gene. The deletion would result in a frameshift after residue 52 that would, if translated, produce 99 novel amino acids from codons 52 to 151 and terminate translation at codon 152 (Gln53ArgfsTer100). The mutation, which segregated with the disorder in the family, was not found in 300 ethnically matched controls. The mutation was filtered against the dbSNP (build 135), 1000 Genomes Project, HapMap, and YanHuang databases. Comparison of both the normal and the predicted mutated OSBPL2 protein structures indicated that the mutation could disrupt the OSBP-related domain, which is considered essential for ligand binding.

.0002 DEAFNESS, AUTOSOMAL DOMINANT 67
OSBPL2, 2-BP DEL, 141TG
By genomewide linkage analysis followed by whole-exome sequencing of affected members of a 6-generation German family with autosomal dominant nonsyndromic hearing loss (DFNA67; 616340), Thoenes et al. (2015) identified a heterozygous 2-bp deletion (c.141_142delTG, NM_144498.2) in the OSBPL2 gene. The mutation was predicted to result in a frameshift and premature termination (Arg50AlafsTer103). The deletion, which segregated with the phenotype in the family, was not present in the dbSNP (build 135), 1000 Genomes Project (build 20110521), or Exome Variant Server (ESP6500) databases.

Tags: 20q13.33