Alternative titles; symbols
HGNC Approved Gene Symbol: VPS13B
SNOMEDCT: 56604005;
Cytogenetic location: 8q22.2 Genomic coordinates (GRCh38) : 8:99,013,274-99,877,580 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q22.2 | Cohen syndrome | 216550 | Autosomal recessive | 3 |
By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1998) cloned COH1 (VPS13B), which they designated KIAA0532. The 3-prime UTR contains 2 Alu repeat sequences. RT-PCR detected COH1 expression in all tissues examined, with highest expression in kidney.
Kolehmainen et al. (2003) identified the COH1 gene within the Cohen syndrome (COH1; 216550) critical region on chromosome 8q22. By in silico analysis, exon prediction, and RT-PCR methods they obtained a full-length COH1 cDNA. The longest COH1 transcript encodes a deduced 4,022-amino acid protein with a complex domain structure, including 10 predicted transmembrane domains, a potential vacuolar targeting motif, endoplasmic reticulum retention signal in the C terminus, and 2 peroxisomal matrix protein targeting signal-2 (PTS2) consensus sequences, one close to the N terminus and the other close to the C terminus. COH1 shows strong homology to the Saccharomyces cerevisiae VPS13 protein, suggesting a role for COH1 in vesicle-mediated sorting and transport of proteins within the cell. Northern blot analysis revealed that COH1 is widely expressed, with differential expression of different transcripts. Transcripts of approximately 2.0 and 5.0 kb were expressed in fetal brain, lung, liver, and kidney, and in all adult tissues analyzed. A transcript of approximately 12 to 14 kb was expressed in prostate, testis, ovary, and colon in the adult. Expression was very low in adult brain tissue.
By searching databases for sequences similar to VPS13A (605978), followed by RT-PCR of lymphoid cell line and brain RNA, Velayos-Baeza et al. (2004) cloned COH1, which they called VPS13B. They identified 2 main variants, variant 1A and variant 2A, and several other variants generated by exon skipping or the use of alternative exons. Variants 1A and 2A both contain exons 1 to 27 and 29 to 62, but variant 1A uses exon 28, while variant 2A uses an alternative exon, exon 28b. EST database analysis indicated that there are at least 6 different 3-prime end splice variants, 3 of which involve alternate exons 17b and 17c. Variant 1A encodes the deduced 4,022-amino acid protein, and variant 2A encodes a deduced 3,997-amino acid protein. VPS13B shares significant similarity with yeast Vps13 and other human VPS13 proteins only in the N and C termini. Northern blot analysis and RT-PCR detected VPS13B expression at variable levels in all tissues examined. Variant 2A was the predominant transcript in all tissues examined except brain and skeletal muscle, in which variant 1A predominated.
By sequence analysis, Kolehmainen et al. (2003) determined that the COH1 gene contains 62 exons and spans a genomic region of approximately 864 kb. The COH1 gene has a complicated pattern of alternative splicing which potentially leads to the use of 4 different termination codons and to 3 additional in-frame, alternatively spliced forms.
Velayos-Baeza et al. (2004) determined that the COH1 gene contains 66 exons, including 4 alternative exons. The translation start codon is in exon 2.
By radiation hybrid analysis, Nagase et al. (1998) mapped the COH1 gene to chromosome 8. Kolehmainen et al. (2003) mapped the COH1 gene to chromosome 8q22. Velayos-Baeza et al. (2004) mapped the mouse Vps13b gene to chromosome 15B3.
Limoge et al. (2015) studied primary fibroblasts from patients with Cohen syndrome (see MOLECULAR GENETICS) as well as SGBS (see 312870) preadipocytes in which expression of VPS13B was knocked down by RNAi, and observed accelerated differentiation into fat cells. This was confirmed by earlier and increased expression of specific adipogenic genes, consequent to the increased response of the cells to insulin stimulation. At the end of the differentiation protocol, these fat cells exhibited decreased AKT2 (164731) phosphorylation after insulin stimulation, suggestive of insulin resistance. Limoge et al. (2015) concluded that VPS13B is an important regulator of adipogenesis, and that defective VPS13B results in increased fat storage and a risk of type 2 diabetes mellitus in patients with Cohen syndrome.
Kolehmainen et al. (2003) identified mutations in the COH1 gene in patients with Cohen syndrome (COH1; 216550). Haplotype analysis of Finnish patients with Cohen syndrome suggested the existence of several different mutations. One haplotype, present in 30 of 40 (75%) disease chromosomes, was always found to be associated with a 2-bp (CT) deletion affecting codons 1116 and 1117 that leads to protein truncation at codon 1124 (607817.0001). Patients in 11 families were homozygous for this mutation. It was also found in heterozygous form in 8 families, in which the patients' other COH1 chromosome carried a different haplotype. In only 1 of these families was a further putative mutation identified, a leu2193-to-arg (607817.0002) missense substitution. Only 1 Finnish family did not carry the most common haplotype and is likely to be homozygous for an as yet unidentified COH1 mutation. The 7 mutations in the COH1 gene identified in 5 non-Finnish patients with Cohen syndrome by Kolehmainen et al. (2003) were predicted to result in premature protein truncation (see, e.g., 607817.0003).
Kolehmainen et al. (2004) reported an extensive genotype-phenotype screen in a total of 76 patients from 59 families with a provisional diagnosis of Cohen syndrome. They found 22 different COH1 mutations, of which 19 were novel, in probands identified by fulfilling 6 or more of the following criteria: developmental delay, microcephaly, typical Cohen syndrome facial gestalt, truncal obesity with slender extremities, overly sociable behavior, joint hypermobility, high myopia and/or retinal dystrophy, and neutropenia. By contrast, no COH1 mutations were found in patients with a provisional diagnosis of Cohen syndrome who were labeled 'Cohen-like.' These patients fulfilled only 5 or fewer of the 8 criteria.
Hennies et al. (2004) described clinical and molecular findings in 20 patients with Cohen syndrome from 12 families, originating from Brazil, Germany, Lebanon, Oman, Poland, and Turkey. All patients were homozygous or compound heterozygous for mutations in COH1. They identified 17 novel mutations, mostly resulting in premature termination codons. The clinical presentation was highly variable. Developmental delay of varying degree, early-onset myopia, joint laxity, and facial dysmorphism were the only features present in all patients; however, retinopathy at school age, microcephaly, and neutropenia, they concluded, are not requisite manifestations of Cohen syndrome.
Falk et al. (2004) described 8 members from 2 large Amish kindreds with features of Cohen syndrome but an atypical facial gestalt. Homozygosity mapping detected linkage to the COH1 gene; sequencing of the gene revealed that all 8 affected individuals were compound homozygous for a 1-bp insertion (9258insT; 607817.0009) and an ile2820-to-thr substitution (I2820T; 607817.0010).
Seifert et al. (2006) studied 24 patients with Cohen syndrome from 16 families of varying ethnic backgrounds and identified 25 different mutations in the COH1 gene, including 9 nonsense mutations, 8 frameshift mutations, 4 verified splice site mutations, 3 larger in-frame deletions, and 1 missense mutation. The authors noted that the vast majority of COH1 mutations found in Cohen syndrome result in premature termination codons.
Katzaki et al. (2007) identified pathogenic mutations in the COH1 gene in 10 Italian patients with Cohen syndrome from 9 families. All patients had characteristic features of the disorder, although with greater variability than reported for Finnish patients. Heterozygous partial COH1 gene deletions were identified in 2 different families.
Parri et al. (2010) used multiplex ligation-dependent probe amplification (MLPA) to analyze the COH1 gene in 14 patients with Cohen syndrome from 11 families, including 4 patients from 3 families previously studied by Katzaki et al. (2007). Parri et al. (2010) detected 12 different mutations, including 6 frameshift, 3 splice site, and 2 nonsense mutations, as well as 1 complex rearrangement. Four patients from 3 Italian families carried the same large deletion (607817.0011) previously identified in Greek patients by Bugiani et al. (2008). Combining these results with those from their previous study, (Katzaki et al., 2007) yielded a total of 21 alleles with point mutations (58%) and 15 alleles with copy number variation (42%); Parri et al. (2010) concluded that deletions and duplications account for a significant percentage of COH1 mutations.
In a 33-year-old woman who exhibited the typical facial gestalt of Cohen syndrome and had neutropenia and retinopathy, but who did not display truncal obesity or mental retardation, Gueneau et al. (2014) identified compound heterozygosity for 2 splice site mutations in the VPS13B gene (607817.0014; 607817.0015). The authors suggested that a dosage effect of residual normal VPS13B protein might explain the incomplete phenotype in this patient.
In 2 Lebanese brothers with Cohen syndrome and the additional features of cutis verticis gyrata and sensorineural deafness, originally reported by Megarbane et al. (2001) as a distinct syndrome, Megarbane et al. (2009) identified a homozygous splicing mutation in the VPS13B gene (607817.0016).
In 26 of 32 patients with Cohen syndrome (COH1; 216550), Kolehmainen et al. (2003) identified homozygosity or heterozygosity for a 2-bp deletion (CT) in the COH1 gene, changing codon 1117 from cysteine to phenylalanine and resulting in a premature termination (I1124X).
In a Finnish family, Kolehmainen et al. (2003) found that Cohen syndrome (COH1; 216550) was associated with compound heterozygosity for the common 2-bp deletion (607817.0001) and a nonsense substitution, leu2193 to arg (L2193R), in the COH1 gene.
In a Belgian patient with Cohen syndrome (COH1; 216550), Kolehmainen et al. (2003) identified homozygosity for an arg2351-to-ter (R2351X) mutation in exon 39 of the COH1 gene.
In a Belgian family with Cohen syndrome (COH1; 216550), Kolehmainen et al. (2004) found homozygosity for an 8978A-G transition in exon 49 of the COH1 gene, resulting in an asn2993-to-ser amino acid change (N2993S).
In a British family with Cohen syndrome (COH1; 216550), Kolehmainen et al. (2004) found homozygosity for a 4471G-T transversion in exon 29 of the COH1 gene, predicted to result in a stop mutation, glu1491 to ter (E1491X).
In a Turkish family with Cohen syndrome (COH1; 216550), Hennies et al. (2004) identified an arg971-to-ter (R971X) mutation resulting from a 2911C-T transition in exon 20 of the COH1 gene.
In an Omani family with Cohen syndrome (COH1; 216550), Hennies et al. (2004) found homozygosity for a 7934G-A transition in exon 43 of the COH1 gene resulting in a gly2645-to-asp (G2645D) amino acid change.
In a Turkish family with Cohen syndrome (COH1; 216550), Hennies et al. (2004) found homozygosity for a 10888C-T transition in exon 56 of the COH1 gene resulting in a gln3630-to-ter (Q3630X) mutation.
In 8 members of 2 large Amish kindreds with features of Cohen syndrome (COH1; 216550) but an atypical facial gestalt, Falk et al. (2004) identified a homozygous 1-bp insertion in exon 51 of the COH1 gene, 9258insT, resulting in a frameshift with a premature stop codon 19 amino acids downstream. All unaffected parents were heterozygous for this change. Patients were also homozygous for an 8459T-C transition in exon 46 of the COH1 gene, resulting in an ile2820-to-thr mutation (I2820T; 607817.0010).
For discussion of the 8459T-C transition in the COH1 gene, resulting in an ile2820-to-thr (I2820T) substitution, that was found in compound heterozygous state in affected members of 2 Amish kindreds with features of Cohen syndrome (COH1; 216550) by Falk et al. (2004), see 607817.0009.
In 14 individuals with Cohen syndrome (COH1; 216550) from an isolated population on 2 small adjacent islands in the eastern part of the Greek archipelago, Bugiani et al. (2008) identified a homozygous deletion of exons 6 through 16 of the COH1 gene, resulting in severe truncation of the predicted protein. Twelve of the patients belonged to a large consanguineous kindred. The phenotype was relatively homogeneous, with common features including moderate to severe mental retardation, slender extremities with narrow hands and feet, joint hypermobility, and the typical facial gestalt. Microcephaly was not as profound as reported in Finnish patients.
In 4 patients with Cohen syndrome from 3 Italian families, including 3 patients from 2 families previously studied by Katzaki et al. (2007), Parri et al. (2010) identified homozygosity or compound heterozygosity (see 607817.0012 and 607817.0013) for the large deletion involving exons 6 through 16 of the VPS13B gene. Haplotype analysis of the 4 Italian patients and 1 of the Greek patients reported by Bugiani et al. (2008) suggested that the recurrent deletion is due to an ancestral founder effect in the Mediterranean area.
In a 6-year-old Italian boy with Cohen syndrome (COH1; 216550), born of consanguineous parents, who was originally reported by Katzaki et al. (2007), Parri et al. (2010) identified compound heterozygosity for a large deletion involving exons 6 through 16 of the VPS13B gene (607817.0011) and a 1-bp deletion (11564delA), predicted to cause a frameshift and a premature termination codon.
In 2 Italian sisters with Cohen syndrome (COH1; 216550), originally reported by Katzaki et al. (2007), Parri et al. (2010) identified compound heterozygosity for 2 large deletions in the VPS13B gene: the exon 6 through 16 deletion (607817.0011) and a deletion involving exons 46 through 50. Analysis of DNA from 2 healthy sibs showed that each unaffected sib was heterozygous for a respective deletion.
In a 33-year-old woman who exhibited the typical facial gestalt of Cohen syndrome and had neutropenia and retinopathy (COH1; 216550), but who did not display truncal obesity or mental retardation, Gueneau et al. (2014) identified compound heterozygosity for 2 splice site mutations in the VPS13B gene: the first was a 1-bp insertion in intron 34 (IVS34+2T_+3AinsT), and the second was a transition in intron 57 (IVS57+2T-C). Each of her parents was heterozygous for 1 of the mutations, neither of which was found in 100 controls. RT-PCR analysis of the intron 34 1-bp insertion did not reveal any abnormally spliced fragments, suggesting retention of intron 34 and creation of a premature termination codon; quantitative RT-PCR was consistent with a nonsense-mediated mRNA decay (NMD) process. RT-PCR analysis of the intron 57 mutation revealed 4 fragments, including 1 normally spliced and 3 abnormally spliced isoforms, the latter showing intron retention and/or exon skipping predicted to result in a premature termination codon or in-frame deletion; quantitative RT-PCR was consistent with NMD. Gueneau et al. (2014) proposed that the patient's atypical phenotype was due to residual production of normal VPS13B RNA and protein by both splice site mutations.
For discussion of the IVS57+2T-C splice site mutation in the VPS13B gene that was found in compound heterozygous state in a patient with Cohen syndrome (COH1; 216550) by Gueneau et al. (2014), see 607817.0014.
In 2 Lebanese brothers with Cohen syndrome (COH1; 216550) and the additional features of cutis verticis gyrata and sensorineural deafness, originally reported by Megarbane et al. (2001) as a distinct syndrome, Megarbane et al. (2009) found linkage of the disorder to chromosome 8q22 and identified a homozygous mutation in the acceptor splice site of intron 51 of the VPS13B gene (c.9406-1G-C, NM_017890). RT-PCR of the corresponding gene segment showed the activation of a cryptic acceptor splice site in exon 52, resulting in a 16-bp deletion in the mRNA predicted to lead to a frameshift and subsequent truncation of the protein to 3,150 residues (Tyr3136ThrfsTer) or an unstable mRNA molecule that is rapidly degraded. The mother and one sister were heterozygous for the mutation, which was not found in 50 unrelated controls. The authors noted that the hearing loss and cutis verticis gyrata could be caused by mutations in a different gene and locus, but that their linkage data did not support the presence of another causative homozygous locus and no deafness gene or locus had been identified on chromosome 8q. Because cutis verticis gyrata is frequently associated with mental retardation, they suggested that it may be a rare manifestation of Cohen syndrome.
Bugiani, M., Gyftodimou, Y., Tsimpouka, P., Lamantea, E., Katzaki, E., d'Adamo, P., Nakou, S., Georgoudi, N., Grigoriadou, M., Tsina, E., Kabolis, N., Milani, D., Pandelia, E., Kokotas, H., Gasparini, P., Giannoulia-Karantana, A., Renieri, A., Zeviani, M., Petersen, M. B. Cohen syndrome resulting from a novel large intragenic COH1 deletion segregating in an isolated Greek island population. Am. J. Med. Genet. 146A: 2221-2226, 2008. [PubMed: 18655112] [Full Text: https://doi.org/10.1002/ajmg.a.32239]
Falk, M. J., Feiler, H. S., Neilson, D. E., Maxwell, K., Lee, J. V., Segall, S. K., Robin, N. H., Wilhelmsen, K. C., Traskelin, A.-L., Kolehmainen, J., Lehesjoki, A.-E., Wiznitzer, M., Warman, M. L. Cohen syndrome in the Ohio Amish. Am. J. Med. Genet. 128A: 23-28, 2004. [PubMed: 15211651] [Full Text: https://doi.org/10.1002/ajmg.a.30033]
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Limoge, F., Faivre, L., Gautier, T., Petit, J.-M., Gautier, E., Masson, D., Jego, G., El Chehadeh-Djebbar, S., Marle, N., Carmignac, V., Deckert, V., Brindisi, M.-C., Edery, P., Ghoumid, J., Blair, E., Lagrost, L., Thauvin-Robinet, C., Duplomb, L. Insulin response dysregulation explains abnormal fat storage and increased risk of diabetes mellitus type 2 in Cohen syndrome. Hum. Molec. Genet. 24: 6603-6613, 2015. [PubMed: 26358774] [Full Text: https://doi.org/10.1093/hmg/ddv366]
Megarbane, A., Slim, R., Nurnberg, G., Ebermann, I., Nurnberg, P., Bolz, H. J. A novel VPS13B mutation in two brothers with Cohen syndrome, cutis verticis gyrata and sensorineural deafness. Europ. J. Hum. Genet. 17: 1076-1079, 2009. [PubMed: 19190672] [Full Text: https://doi.org/10.1038/ejhg.2008.273]
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Parri, V., Katzaki, E., Uliana, V., Scionti, F., Tita, R., Artuso, R., Longo, I., Boschloo, R., Vijzelaar, R., Selecorni, A., Brancati, F., Dallapiccola, B., and 15 others. High frequency of COH1 intragenic deletions and duplications detected by MLPA in patients with Cohen syndrome. Europ. J. Hum. Genet. 18: 1133-1140, 2010. [PubMed: 20461111] [Full Text: https://doi.org/10.1038/ejhg.2010.59]
Seifert, W., Holder-Espinasse, M., Spranger, S., Hoeltzenbein, M., Rossier, E., Dollfus, H., Lacombe, D., Verloes, A., Chrzanowska, K. H., Maegawa, G. H. B., Chitayat, D., Kotzot, D., Huhle, D., Meinecke, P., Albrecht, B., Mathijssen, I., Leheup, B., Raile, K., Hennies, H. C., Horn, D. Mutational spectrum of COH1 and clinical heterogeneity in Cohen syndrome. (Letter) J. Med. Genet. 43: e22, 2006. Note: Electronic Article. [PubMed: 16648375] [Full Text: https://doi.org/10.1136/jmg.2005.039867]
Velayos-Baeza, A., Vettori, A., Copley, R. R., Dobson-Stone, C., Monaco, A. P. Analysis of the human VPS13 gene family. Genomics 84: 536-549, 2004. [PubMed: 15498460] [Full Text: https://doi.org/10.1016/j.ygeno.2004.04.012]