VPS13B

Last updated
VPS13B
Identifiers
Aliases VPS13B , CHS1, COH1, vacuolar protein sorting 13 homolog B
External IDs OMIM: 607817 MGI: 1916380 HomoloGene: 49516 GeneCards: VPS13B
Orthologs
SpeciesHumanMouse
Entrez

157680

666173

Ensembl

ENSG00000132549

ENSMUSG00000037646

UniProt

Q7Z7G8

Q80TY5

RefSeq (mRNA)

NM_015243
NM_017890
NM_152564
NM_181661
NM_184042

NM_177151

RefSeq (protein)

NP_056058
NP_060360
NP_689777
NP_858047

NP_796125

Location (UCSC) Chr 8: 99.01 – 99.88 Mb Chr 15: 35.37 – 35.93 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
vacuolar protein sorting 13B (yeast)
Identifiers
SymbolVPS13B
Alt. symbolsCHS1, COH1
NCBI gene 157680
HGNC 2183
OMIM 607817
RefSeq NM_184042
UniProt Q7Z7G8
Other data
Locus Chr. 8 q22-q23
Search for
Structures Swiss-model
Domains InterPro

Intermembrane lipid transfer protein VPS13B, also known as vacuolar protein sorting-associated 13B, and Cohen syndrome protein 1 is a protein that in humans is encoded by the VPS13B gene. It is a giant protein associated with the Golgi apparatus that is believed to be involved in post-Golgi apparatus sorting and trafficking. [5] Mutations in the human VPS13B gene cause Cohen syndrome.

Contents

VPS13B gene is also referred to as CHS1, COH1, KIAA0532, [6] and DKFZp313I0811. [7]

The cytogenetic location of the human VPS13B gene is 8q22, which is the long arm of chromosome eight at position 22.2. Various splice variants encoding isoforms have been identified. The canonical form of the expressed protein encoded by the human VPS13B gene has 3997 amino acids. [6]

Gene

The VPS13B gene is located on chromosome 8q22. Deletions in this chromosome are associated with Cohen syndrome, which is why this gene is alternatively called COH1. [8] The gene is made up of 66 exons, four of which are alternative. [9] The pattern of alternative splicing in the VS13B gene is complex in the analyzed regions including exons 28B and 28. This eventually causes four termination codons and three alternatively spliced forms to be in use. [10] Exon 2 is where its translation start codon occurs. [9]  VPS13B is a large gene: it spans a genomic DNA sequence region of about 864 kilobase pairs, or 846,000 base pairs. [9] The VPS13B gene is widely expressed, especially in the prostate, testis, ovary, and colon with transcripts of about 12 to 14 kilobase pairs. It is also expressed in the fetal brain, liver, and kidney, with transcripts of about 2.0 to 5.0 kilobase pairs. Expression in the adult brain is very minimal. [11] Variants 1A and 2A are the principal variants of the gene that encode 4,022 and 39,997 amino acid proteins, respectively. [8] Two Alu repeat sequences are present in the 3' untranslated regions. [12]

Nomenclature

The VPS13B gene is also known as: [13]

Function

Proteins produced from the VPS13B gene are part of the Golgi apparatus. [13] They are also responsible for sorting and transporting of proteins inside of the cell. [13] The VPS13B protein is important because it plays an important role in the function of normal growth, the development of neurons, and the development of adipocytes. [13] This protein may also play a role in the development of the function for eyes, the hematological system, and the central nervous system; and in the storage and distribution of fats in the body. [14] VPS13B is found at locus 8q22.2. [13] This means that the VPS13B gene is located on chromosome 8 at position 22.2 on the long q arm at 8q22.2. [13] The VPS13B protein is composed of 4,022 amino acids and might have a total of ten trans-membrane domains and a complex pattern of functional motifs. [15]

Presently, the VPS13B gene is recognized as a protein-coding gene that produces the VPS13B protein. [16] The VPS13B protein has been associated with the Golgi apparatus and intracellular processes such as protein modification, protein organization, and protein distribution. [17] It has also been speculated that the VPS13B protein may influence the development of certain somatic cells and body systems, and may be involved in the storing and allocation of fats in humans. [6] [17]

Mutations in the VPS13B gene can result in the abnormal function of the VPS13B protein. Mutations within the gene have been linked as a potential factor in Cohen syndrome and autism. [17] [18] [19] [20] In Cohen syndrome, it is thought that deletion mutations in the gene alter the shape of the VPS13B protein, resulting in a shorter, nonfunctioning protein. [17] [19] Altered VPS13B protein is then unable to function properly due to these genetic changes, thus resulting in an obstruction of regular processes. [17] Studies have also linked mutations in the VPS13B gene to osteoporosis. [8] An association between an increase of the VPS13B copy number variants and a lower bone mineral density in adults has been found. [8] Still, the normal, definitive function of the VPS13B gene is unknown, as are the specific implications of its mutated forms.

Clinical significance

Over 150 types of different mutations in the VPS13B gene have been identified in individuals diagnosed with Cohen syndrome. [13] A deletion in the VPS13B gene causes a premature stop signal in the instructions for making the VPS13B protein, causing the protein to become abnormally short and nonfunctional. [13] When this happens, the nonfunctional protein causes the Golgi apparatus not to work properly and stops normal glycosylation. [13]

Cohen syndrome

COH1 depletion in HeLa cells by RNA interference disrupts normal Golgi organization. Deletions in this gene is a cause of autosomal recessive Cohen syndrome. Fibroblasts from Cohen syndrome patients also have abnormal Golgi. [21] Cohen syndrome patients have been shown to have defective protein glycosylation, [22] which is a major function of the Golgi, thus supporting the suggestion that Golgi dysfunction contributes to Cohen syndrome pathology. [21]

Cohen syndrome is a very rare inherited genetic condition which has been diagnosed in almost one thousand people worldwide. It occurs when there is a biallelic mutation in the VPS13B gene. This disorder causes a variety of symptoms that never ease. Microcephaly, hypotonia, worsening eyesight, retinal dystrophy, delayed puberty, hyper mobility, and obesity are just a few examples. People with this syndrome have distinct facial features. They have bulging noses, unusually shaped eyes, thick hair, narrow hands and feet, and long, thin fingers. [23]

The symptoms of Cohen syndrome begin to show at a very young age. At birth, newborns may show no symptoms at all, but once they start to develop their facial characteristics, it will be noticeable. [24] It begins with failure to thrive in infants and children, and then the developmental delays start to show: microcephaly, retinochorodial dystrophy, psychomotor retardation, high myopia, neutropenia, joint hyper mobility and the distinct facial features start forming. During the teenage and adolescent years, short stature and obesity start to become concerns. Almost 30% of people with this syndrome are non-verbal and illiterate. [25] In many instances where speech delay is prominent in this syndrome, aphthous ulcers develop inside the mouth, causing pain. Many Cohen syndrome-affected people start to lose their eyesight by age 30. Although Cohen syndrome does not decrease life expectancy, it reduces quality of life due to the inability to speak and/or see. [24] Patients with this syndrome are also known to suffer from seizures, narrow hands and feet, and growth hormone deficiencies. [26]

Cohen syndrome is an autosomal recessive disorder that is characterized by mainly facial dysmorphism, microcephaly, joint laxity and intermittent neutropenia. Cohen syndrome is inherited in an autosomal recessive manner, which means there is a 50% chance of being a carrier. Children of people with this syndrome are carriers for the syndrome. [19] 75% of individuals with Cohen syndrome in the Finnish population have a mutation in both copies of the gene. Mutations in the gene VPS13B only occur in a small number of families, outside of Finnish and Amish groups. [17]

Neutropenia

Another disease that the VPS13B gene contributes to is neutropenia, which involves a low concentration of neutrophils, [27] a type of white blood cell. This causes the affected person to be more susceptible to infections and disease. [27] Although this is a genetic disease, it can also be caused by certain medications and sometimes bone marrow.[ clarification needed ] [27]

Sutton disease 2

Sutton disease is a chronic inflammatory disease that creates painful ulcers in the mouth. [28] These can be different size and cause different amounts of pain. The disease is more commonly called canker sores. [28]

Ewing sarcoma

Ewing sarcoma is a cancerous tumor in the bones or soft tissues, such as cartilage or nerves. [29] It usually presents in children, teens and young adults. [29] Other diseases are similar to Ewing sarcoma, but this one is the only one that has the VPS13B gene. [29]

Microcephaly

Microcephaly is a medical condition in which the head is misshapen and smaller than normal. [30] In most cases, people with microcephaly experience seizures, development delays, and problems with movement, balance, and eating. Hearing loss and losing vision can occur. [30]

Other

Syndromic autism is also associated with this gene, [7] as is intellectual disability. [31] [32]

Related Research Articles

<span class="mw-page-title-main">Microcephaly</span> Condition in which the head is small due to an underdeveloped brain

Microcephaly is a medical condition involving a smaller-than-normal head. Microcephaly may be present at birth or it may develop in the first few years of life. Brain development is often affected; people with this disorder often have an intellectual disability, poor motor function, poor speech, abnormal facial features, seizures and dwarfism.

<span class="mw-page-title-main">Chromosome 8</span> Human chromosome

Chromosome 8 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 8 spans about 146 million base pairs and represents between 4.5 and 5.0% of the total DNA in cells.

<span class="mw-page-title-main">Chromosome 15</span> Human chromosome

Chromosome 15 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 15 spans about 99.7 million base pairs and represents between 3% and 3.5% of the total DNA in cells. Chromosome 15 is an acrocentric chromosome, with a very small short arm, which contains few protein coding genes among its 19 million base pairs. It has a larger long arm that is gene rich, spanning about 83 million base pairs.

<span class="mw-page-title-main">Chromosome 16</span> Human chromosome

Chromosome 16 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 16 spans about 96 million base pairs and represents just under 3% of the total DNA in cells.

<span class="mw-page-title-main">ATP7A</span> Protein-coding gene in humans

ATP7A, also known as Menkes' protein (MNK), is a copper-transporting P-type ATPase which uses the energy arising from ATP hydrolysis to transport Cu(I) across cell membranes. The ATP7A protein is a transmembrane protein and is expressed in the intestine and all tissues except liver. In the intestine, ATP7A regulates Cu(I) absorption in the human body by transporting Cu(I) from the small intestine into the blood. In other tissues, ATP7A shuttles between the Golgi apparatus and the cell membrane to maintain proper Cu(I) concentrations in the cell and provides certain enzymes with Cu(I). The X-linked, inherited, lethal genetic disorder of the ATP7A gene causes Menkes disease, a copper deficiency resulting in early childhood death.

<span class="mw-page-title-main">TBX1</span> Protein-coding gene in the species Homo sapiens

T-box transcription factor TBX1 also known as T-box protein 1 and testis-specific T-box protein is a protein that in humans is encoded by the TBX1 gene. Genes in the T-box family are transcription factors that play important roles in the formation of tissues and organs during embryonic development. To carry out these roles, proteins made by this gene family bind to specific areas of DNA called T-box binding element (TBE) to control the expression of target genes.

<span class="mw-page-title-main">Cohen syndrome</span> Medical condition

Cohen syndrome is a very rare autosomal recessive genetic disorder with varied expression, characterised by obesity, intellectual disability, distinct craniofacial abnormalities and potential ocular dysfunction.

<span class="mw-page-title-main">22q13 deletion syndrome</span> Rare genetic syndrome

22q13 deletion syndrome, also known as Phelan–McDermid syndrome (PMS), is a genetic disorder caused by deletions or rearrangements on the q terminal end of chromosome 22. Any abnormal genetic variation in the q13 region that presents with significant manifestations (phenotype) typical of a terminal deletion may be diagnosed as 22q13 deletion syndrome. There is disagreement among researchers as to the exact definition of 22q13 deletion syndrome. The Developmental Synaptopathies Consortium defines PMS as being caused by SHANK3 mutations, a definition that appears to exclude terminal deletions. The requirement to include SHANK3 in the definition is supported by many but not by those who first described 22q13 deletion syndrome.

<span class="mw-page-title-main">GABRB3</span> Protein-coding gene in the species Homo sapiens

Gamma-aminobutyric acid receptor subunit beta-3 is a protein that in humans is encoded by the GABRB3 gene. It is located within the 15q12 region in the human genome and spans 250kb. This gene includes 10 exons within its coding region. Due to alternative splicing, the gene codes for many protein isoforms, all being subunits in the GABAA receptor, a ligand-gated ion channel. The beta-3 subunit is expressed at different levels within the cerebral cortex, hippocampus, cerebellum, thalamus, olivary body and piriform cortex of the brain at different points of development and maturity. GABRB3 deficiencies are implicated in many human neurodevelopmental disorders and syndromes such as Angelman syndrome, Prader-Willi syndrome, nonsyndromic orofacial clefts, epilepsy and autism. The effects of methaqualone and etomidate are mediated through GABBR3 positive allosteric modulation.

<span class="mw-page-title-main">SALL1</span> Protein-coding gene in the species Homo sapiens

Sal-like 1 (Drosophila), also known as SALL1, is a protein which in humans is encoded by the SALL1 gene. As the full name suggests, it is one of the human versions of the spalt (sal) gene known in Drosophila.

<span class="mw-page-title-main">VPS13A</span> Protein-coding gene in the species Homo sapiens

VPS13A is a protein that in humans is encoded by the VPS13A gene.

<span class="mw-page-title-main">COX10</span> Mammalian protein found in Homo sapiens

Protoheme IX farnesyltransferase, mitochondrial is an enzyme that in humans is encoded by the COX10 gene. Cytochrome c oxidase (COX), the terminal component of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. This component is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may function in the regulation and assembly of the complex. This nuclear gene, COX10, encodes heme A: farnesyltransferase, which is not a structural subunit but required for the expression of functional COX and functions in the maturation of the heme A prosthetic group of COX. A gene mutation, which results in the substitution of a lysine for an asparagine (N204K), is identified to be responsible for cytochrome c oxidase deficiency. In addition, this gene is disrupted in patients with CMT1A duplication and with HNPP deletion.

<span class="mw-page-title-main">SHANK3</span> Protein-coding gene in the species Homo sapiens

SH3 and multiple ankyrin repeat domains 3 (Shank3), also known as proline-rich synapse-associated protein 2 (ProSAP2), is a protein that in humans is encoded by the SHANK3 gene on chromosome 22. Additional isoforms have been described for this gene but they have not yet been experimentally verified.

<span class="mw-page-title-main">VPS52</span> Protein-coding gene in the species Homo sapiens

Vacuolar protein sorting-associated protein 52 homolog is a protein that in humans is encoded by the VPS52 gene.

<span class="mw-page-title-main">VPS33A</span> Protein-coding gene in the species Homo sapiens

Vacuolar protein sorting-associated protein 33A is a protein that in humans is encoded by the VPS33A gene.

X-linked intellectual disability refers to medical disorders associated with X-linked recessive inheritance that result in intellectual disability.

Wrinkly skin syndrome(WSS) is a rare genetic condition characterized by sagging, wrinkled skin, low skin elasticity, and delayed fontanelle (soft spot) closure, along with a range of other symptoms. The disorder exhibits an autosomal recessive inheritance pattern with mutations in the ATP6V0A2 gene, leading to abnormal glycosylation events. There are only about 30 known cases of WSS as of 2010. Given its rarity and symptom overlap with other dermatological conditions, reaching an accurate diagnosis is difficult and requires specialized dermatological testing. Limited treatment options are available but long-term prognosis is variable from patient to patient, based on individual case studies. Some skin symptoms recede with increasing age, while progressive neurological advancement of the disorder causes seizures and mental deterioration later in life for some patients.

<span class="mw-page-title-main">G6PC3</span> Protein-coding gene in the species Homo sapiens

Glucose-6-phosphatase 3, also known as glucose-6-phosphatase beta, is an enzyme that in humans is encoded by the G6PC3 gene.

<span class="mw-page-title-main">VPS53</span> Protein-coding gene in the species Homo sapiens

Vacuolar protein sorting 53 homolog is a protein that in humans is encoded by the VPS53 gene.

<span class="mw-page-title-main">17q12 microdeletion syndrome</span> Rare genetic anomaly in humans

17q12 microdeletion syndrome, also known as 17q12 deletion syndrome, is a rare chromosomal anomaly caused by the deletion of a small amount of material from a region in the long arm of chromosome 17. It is typified by deletion of the HNF1B gene, resulting in kidney abnormalities and renal cysts and diabetes syndrome. It also has neurocognitive effects, and has been implicated as a genetic factor for autism and schizophrenia.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000132549 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000037646 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ "Vacuolar protein sorting-associated protein 13B (IPR039782)". InterPro. EMBL-EBI. Retrieved 2018-11-11.
  6. 1 2 3 "VPS13B vacuolar protein sorting 13 homolog B [Homo sapiens (human)] - Gene - NCBI". Entrez Gene. National Center for Biotechnology Information. Retrieved 2018-11-07.
  7. 1 2 "Gene: VPS13B". SFARI Gene. Retrieved 2018-11-08.
  8. 1 2 3 4 Deng FY, Zhao LJ, Pei YF, Sha BY, Liu XG, Yan H, Wang L, Yang TL, Recker RR, Papasian CJ, Deng HW (April 2010). "Genome-wide copy number variation association study suggested VPS13B gene for osteoporosis in Caucasians". Osteoporosis International. 21 (4): 579–87. doi:10.1007/s00198-009-0998-7. PMC   2924432 . PMID   19680589.
  9. 1 2 3 Velayos-Baeza A, Vettori A, Copley RR, Dobson-Stone C, Monaco AP (September 2004). "Analysis of the human VPS13 gene family". Genomics. 84 (3): 536–49. doi:10.1016/j.ygeno.2004.04.012. PMID   15498460.
  10. ↑ Kolehmainen J, Black GC, Saarinen A, Chandler K, Clayton-Smith J, Träskelin AL, et al. (June 2003). "Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and intracellular protein transport". American Journal of Human Genetics. 72 (6): 1359–69. doi:10.1086/375454. PMC   1180298 . PMID   12730828.
  11. ↑ "CTGA DetailsCentre for Arab Genomic Studies". Centre for Arab Genomic Studies. 2018.
  12. ↑ Tadmour G (2005). "COH1 Gene" (PDF). Centre for Arab Genomic Studies.[ permanent dead link ]
  13. 1 2 3 4 5 6 7 8 9 "VPS13B gene". Genetics Home Reference. Retrieved 2018-11-11.
  14. ↑ "VPS13B Human Gene". GeneCards. Retrieved 2018-11-11.
  15. ↑ "VPS13B (COH1) Gene Analysis in Cohen Syndrome" (PDF). GeneDx . December 2016. Archived from the original (PDF) on November 11, 2018. Retrieved November 4, 2018.
  16. ↑ "Gene: VPS13B (ENSG00000132549) Homo sapiens". GRCh37 Archive browser 94. Retrieved 2018-11-09.
  17. 1 2 3 4 5 6 "VPS13B gene". Genetics Home Reference. Retrieved 2018-11-07.
  18. ↑ Ionita-Laza I, Capanu M, De Rubeis S, McCallum K, Buxbaum JD (December 2014). "Identification of rare causal variants in sequence-based studies: methods and applications to VPS13B, a gene involved in Cohen syndrome and autism". PLOS Genetics. 10 (12): e1004729. doi: 10.1371/journal.pgen.1004729 . PMC   4263785 . PMID   25502226.
  19. 1 2 3 Balikova I, Lehesjoki AE, de Ravel TJ, Thienpont B, Chandler KE, Clayton-Smith J, Träskelin AL, Fryns JP, Vermeesch JR (September 2009). "Deletions in the VPS13B (COH1) gene as a cause of Cohen syndrome". Human Mutation. 30 (9): E845-54. doi: 10.1002/humu.21065 . PMID   19533689. S2CID   45212182.
  20. ↑ Yu TW, Chahrour MH, Coulter ME, Jiralerspong S, Okamura-Ikeda K, Ataman B, et al. (January 2013). "Using whole-exome sequencing to identify inherited causes of autism". Neuron. 77 (2): 259–73. doi:10.1016/j.neuron.2012.11.002. PMC   3694430 . PMID   23352163.
  21. 1 2 Seifert W, Kühnisch J, Maritzen T, Horn D, Haucke V, Hennies HC (October 2011). "Cohen syndrome-associated protein, COH1, is a novel, giant Golgi matrix protein required for Golgi integrity". The Journal of Biological Chemistry. 286 (43): 37665–75. doi: 10.1074/jbc.M111.267971 . PMC   3199510 . PMID   21865173.
  22. ↑ Duplomb L, Duvet S, Picot D, Jego G, El Chehadeh-Djebbar S, Marle N, et al. (May 2014). "Cohen syndrome is associated with major glycosylation defects". Human Molecular Genetics. 23 (9): 2391–9. doi: 10.1093/hmg/ddt630 . PMID   24334764.
  23. ↑ "Cohen syndrome". Genetics Home Reference. Retrieved 2018-11-09.
  24. 1 2 "Cohen syndrome". Orphanet: The portal for rare diseases and orphan drugs. Paris, France: INSERM US14. Retrieved 2018-11-10.
  25. ↑ Wang H, Falk MJ, Wensel C, Traboulsi E (1993). "Cohen Syndrome". In Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A (eds.). GeneReviews. Seattle (WA): University of Washington, Seattle. PMID   20301655 . Retrieved 2018-11-10.
  26. ↑ Online Mendelian Inheritance in Man (OMIM): Cohen Syndrome; COH1 - 216550
  27. 1 2 3 "Neutropenia disease: Malacards - Research Articles, Drugs, Genes, Clinical Trials" . Retrieved 2018-11-11.
  28. 1 2 "Sutton Disease 2 disease". Malacards - Research Articles, Drugs, Genes, Clinical Trials. Retrieved 2018-11-11.
  29. 1 2 3 "Ewing Sarcoma disease". Malacards - Research Articles, Drugs, Genes, Clinical Trials. Retrieved 2018-11-11.
  30. 1 2 "Microcephaly disease". Malacards - Research Articles, Drugs, Genes, Clinical Trials. Retrieved 2018-11-11.
  31. ↑ Netherlands. "Disease #00139 - Global Variome shared LOVD". Leiden Open Variation Database (LOVD). Retrieved 2018-11-09.
  32. ↑ "Inherited autism mutations found via genomic sequencing in Mideast families". Vector. Boston Children’s Hospital. 2013-01-25. Archived from the original on 2020-09-19. Retrieved 2018-11-09.
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