Alternative titles; symbols
HGNC Approved Gene Symbol: VPS13A
SNOMEDCT: 66881004;
Cytogenetic location: 9q21.2 Genomic coordinates (GRCh38) : 9:77,177,534-77,421,537 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q21.2 | Choreoacanthocytosis | 200150 | Autosomal recessive | 3 |
In the choreoacanthocytosis (200150) critical region on chromosome 9q, Rampoldi et al. (2001) identified the VPS13A gene, which they called CHAC. They identified 2 splice variants: transcript A, which contains exons 1 to 68 and 70 to 73 and encodes a 3,174-amino acid protein, and transcript B, which contains exons 1 to 69 and encodes a 3,095-amino acid protein. Northern blot analysis detected 2 bands of high molecular mass corresponding to the 2 splice variants in all tissues analyzed. Additionally, RT-PCR detected expression in the erythrocyte precursor cell line K562. Rampoldi et al. (2001) showed that the CHAC gene encodes an evolutionarily conserved protein, which may be involved in protein sorting.
Independently, Ueno et al. (2001) identified the VPS13A gene and found that it encodes a 3,096-amino acid protein, which they termed chorein. Northern blot analysis detected a 10-kb transcript in brain, heart, skeletal muscle, and kidney.
By EST database analysis and RT-PCR of lymphoid cell line and brain RNA, Velayos-Baeza et al. (2004) identified several additional splice variants of VPS13A generated by exon skipping or utilization of alternative internal exons. Northern blot analysis and RT-PCR detected VPS13A expression at variable levels in all tissues examined, and transcript encoding the 3,174-amino acid protein was the major variant.
Rampoldi et al. (2001) determined that the VPS13A gene contains 73 exons and spans 250 kb. Velayos-Baeza et al. (2004) identified 5 additional alternative exons in the VPS13A gene, exons 7b, 31b, 34b, 68b, and 69b, but 3 of these, exons 31b, 34b, and 69b, have stop codons in all 3 reading frames.
Rampoldi et al. (2001) mapped the VPS13A gene to chromosome 9q21-q22. Velayos-Baeza et al. (2004) mapped the mouse Vps13a gene to chromosome 19A.
In affected members of 11 families with choreoacanthocytosis (CHAC; 200150), Rampoldi et al. (2001) identified 16 different mutations in the VPS13A gene (see, e.g., 605978.0001).
In 4 affected patients from 3 Japanese pedigrees with choreoacanthocytosis, Ueno et al. (2001) identified a homozygous deletion in the coding region of the VPS13A gene (605978.0003).
Among 43 patients with choreoacanthocytosis, Dobson-Stone et al. (2002) identified 57 different mutations distributed throughout the CHAC gene (see, e.g., 605978.0004). In 7 patients, only 1 heterozygous mutation was found; in 4 patients, no disease mutations were found. The authors noted that small gene deletions or rearrangements may not have been detected in these patients.
Dobson-Stone et al. (2005) stated that 75 different mutations in the VPS13A gene had been identified in 58 probands with choreoacanthocytosis.
In a patient with choreoacanthocytosis (CHAC; 200150), Rampoldi et al. (2001) found compound heterozygosity for a 269T-A transversion in exon 4 of the VPS13A gene and an insertion of a T between nucleotides 6404 and 6405 in exon 48. The mutations resulted in an ile90-to-lys (I90K) amino acid change and a frameshift, respectively.
See 605978.0001 and Rampoldi et al. (2001).
In affected members of 3 Japanese families with choreoacanthocytosis (CHAC; 200150), Ueno et al. (2001) identified a homozygous 260-bp deletion in the VPS13A gene, leading to a truncated protein. The families originated from a small area in Japan, and haplotype analysis indicated a founder effect. Some of the patients' parents, who were heterozygous for the mutation, showed a slight degree of acanthocytosis in peripheral blood but no distinct neurologic abnormalities except for cryptogenic abducens palsy in 1 parent.
In 3 patients with choreoacanthocytosis, Dobson-Stone et al. (2002) identified a 622C-T change in exon 9 of the CHAC gene, resulting in an arg208-to-ter nonsense substitution (R208X). One patient was homozygous for the mutation and 2 others were compound heterozygous for R208X and another CHAC mutation. The R208X mutation had previously been reported by Rampoldi et al. (2001) in a family with choreoacanthocytosis.
In 2 affected sibs from a Japanese family with choreoacanthocytosis (CHAC; 200150) with apparent autosomal dominant inheritance, Saiki et al. (2003) identified a heterozygous G-to-A transition at the last nucleotide of exon 57 of the CHAC gene, predicted to induce skipping of exon 57 and premature termination of the protein. The mutation was not detected in their unaffected mother. Family history revealed that 3 other living family members were affected and 2 deceased members were believed to be affected. All 5 living affected members showed acanthocytosis (approximately 15-20%) and involuntary movements. In an erratum, the authors stated that an error in sequencing had occurred and the inheritance pattern should have been reported as autosomal recessive (pseudodominant). Tomiyasu et al. (2011) identified the 2 mutations in the VPS13A gene in this family: an 8035G-A transition in exon 57, causing a frameshift and premature termination (Ile2652HisfsTer12), and a 1305G-A transition in exon 15, resulting in a trp435-to-ter (W435X; 605978.0010) substitution; the latter mutation was also identified in the unaffected mother.
In 2 unrelated males of Ashkenazi Jewish descent with choreoacanthocytosis (CHAC; 200150), Lossos et al. (2005) identified a homozygous 1-bp deletion (6059delC) in exon 46 of the VPS13A gene, predicted to result in premature termination of the protein.
In an Iraqi Jewish woman with choreoacanthocytosis (CHAC; 200150), Lossos et al. (2005) identified a homozygous 7-kb deletion spanning exon 23 of the VPS13A gene. She had trichotillomania and anxiety but little neuromuscular involvement.
In affected members of 3 French Canadian families with choreoacanthocytosis (CHAC; 200150), Dobson-Stone et al. (2005) identified a homozygous 37-kb deletion in the VPS13A gene, resulting in the deletion of exons 70 through 73. The deletion also encompassed the 2 terminal exons of the neighboring GNA14 gene (604397). Haplotype analysis indicated a founder effect.
In 2 Mexican mestizo sisters, born of consanguineous parents, with choreoacanthocytosis (CHAC; 200150), Ruiz-Sandoval et al. (2007) identified a homozygous 2-bp duplication (3556dupAC) in exon 33 of the VPS13A gene, resulting in a frameshift and premature termination. The proband had onset at age 32 years and showed severe progression of the disorder; at age 42, she was emaciated, anarthric, and reactive only to simple commands. In contrast, her sister had onset at age 45 years and primarily showed motor and verbal tics, paranoid behavior, and depression.
For discussion of the 1305G-A transition in exon 15 of the VPS13A gene, resulting in a trp435-to-ter (W435X) substitution, that was found in compound heterozygous state in 2 affected sibs from a Japanese family with choreoacanthocytosis (CHAC; 200150) by Tomiyasu et al. (2011), see 605978.0005.
Dobson-Stone, C., Danek, A., Rampoldi, L., Hardie, R. J., Chalmers, R. M., Wood, N. W., Bohlega, S., Dotti, M. T., Federico, A., Shizuka, M., Tanaka, M., Watanabe, M., and 32 others. Mutational spectrum of the CHAC gene in patients with chorea-acanthocytosis. Europ. J. Hum. Genet. 10: 773-781, 2002. [PubMed: 12404112] [Full Text: https://doi.org/10.1038/sj.ejhg.5200866]
Dobson-Stone, C., Velayos-Baeza, A., Jansen, A., Andermann, F., Dubeau, F., Robert, F., Summers, A., Lang, A. E., Chouinard, S., Danek, A., Andermann, E., Monaco, A. P. Identification of a VPS13A founder mutation in French Canadian families with chorea-acanthocytosis. Neurogenetics 6: 151-158, 2005. [PubMed: 15918062] [Full Text: https://doi.org/10.1007/s10048-005-0220-9]
Lossos, A., Dobson-Stone, C., Monaco, A. P., Soffer, D., Rahamim, E., Newman, J. P., Mohiddin, S., Fananapazir, L., Lerer, I., Linetsky, E., Reches, A., Argov, Z., Abramsky, O., Gadoth, N., Sadeh, M., Gomori, J. M., Boher, M., Meiner, V. Early clinical heterogeneity in choreoacanthocytosis. Arch. Neurol. 62: 611-614, 2005. [PubMed: 15824261] [Full Text: https://doi.org/10.1001/archneur.62.4.611]
Rampoldi, L., Dobson-Stone, C., Rubio, J. P., Danek, A., Chalmers, R. M., Wood, N. W., Verellen, C., Ferrer, X., Malandrini, A., Fabrizi, G. M., Brown, R., Vance, J., Pericak-Vance, M., Rudolf, G., Carre, S., Alonso, E., Manfredi, M., Nemeth, A. H., Monaco, A. P. A conserved sorting-associated protein is mutant in chorea-acanthocytosis. Nature Genet. 28: 119-120, 2001. [PubMed: 11381253] [Full Text: https://doi.org/10.1038/88821]
Ruiz-Sandoval, J. L., Garcia-Navarro, V., Chiquete, E., Dobson-Stone, C., Monaco, A. P., Alvarez-Palazuelos, L. E., Padilla-Martinez, J. J., Barrera-Chairez, E., Rodriguez-Figueroa, E. I., Perez-Garcia, G. Choreoacanthocytosis in a Mexican family. Arch. Neurol. 64: 1661-1664, 2007. [PubMed: 17998451] [Full Text: https://doi.org/10.1001/archneur.64.11.1661]
Saiki, S., Sakai, K., Kitagawa, Y., Saiki, M., Kataoka, S., Hirose, G. Mutation in the CHAC gene in a family of autosomal dominant chorea-acanthocytosis. Neurology 61: 1614-1616, 2003. Note: Erratum: Neurology 77: 701 only, 2011. [PubMed: 14663054] [Full Text: https://doi.org/10.1212/01.wnl.0000096172.26601.02]
Tomiyasu, A., Nakamura, M., Ichiba, M., Ueno, S., Saiki, S., Morimoto, M., Kobal, J., Kageyama, Y., Inui, T., Wakabayashi, K., Yamada, T., Kanemori, Y., and 22 others. Novel pathogenic mutations and copy number variations in the VPS13A gene in patients with chorea-acanthocytosis. Am. J. Med. Genet. 156B: 620-631, 2011. [PubMed: 21598378] [Full Text: https://doi.org/10.1002/ajmg.b.31206]
Ueno, S., Maruki, Y., Nakamura, M., Tomemori, Y., Kamae, K., Tanabe, H., Yamashita, Y., Matsuda, S., Kaneko, S., Sano, A. The gene encoding a newly discovered protein, chorein, is mutated in chorea-acanthocytosis. Nature Genet. 28: 121-122, 2001. [PubMed: 11381254] [Full Text: https://doi.org/10.1038/88825]
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]