Alternative titles; symbols
HGNC Approved Gene Symbol: HACD1
Cytogenetic location: 10p12.33 Genomic coordinates (GRCh38): 10:17,589,032-17,617,374 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10p12.33 | Congenital myopathy 11 | 619967 | Autosomal recessive | 3 |
Long chain fatty acids (LCFAs) can be converted to very long chain fatty acids (VLCFAs) by endoplasmic reticulum (ER) membrane-bound enzymes in a 4-step cycle of condensation, reduction, dehydration, and further reduction, with 2 carbons added per cycle. PTPLA belongs to a family of enzymes that catalyze the dehydration step of VLCFA synthesis (summary by Ikeda et al., 2008).
Uwanogho et al. (1999) cloned human PTPLA from an amplified adult heart cDNA library, using the murine Ptpla as a probe. Genomic clones containing PTPLA were isolated by hybridizing the human PTPLA cDNA to a human PAC library (RPC1). From the first of 2 in-frame AUG codons, the conceptual translation of PTPLA yielded a protein of 287 amino acids with a molecular mass of 33 kD. A putative SV40-like nuclear localization signal was identified at the N terminus. In situ hybridization of mouse embryos detected Ptpla transcripts throughout myogenesis as well as in cardiac myocytes and in liver. By Northern blot analysis of human tissues, Li et al. (2000) demonstrated that PTPLA is preferentially expressed in adult and fetal heart; a low level was expressed in skeletal and smooth muscle tissues and virtually none in other tissues tested.
Ikeda et al. (2008) found that epitope-tagged HACD1 was expressed in the ER of transfected HeLa cells.
Uwanogho et al. (1999) suggested that the substitution of an essential arginine by proline within the presumed active site of PTPLA may render the protein inactive, making PTPLA an antiphosphatase that competitively antagonizes PTPs.
Ikeda et al. (2008) found that expression of fluorescence-tagged human HACD1 rescued the lethal phenotype in a yeast strain deficient in 3-hydroxyacyl-CoA dehydratase activity and restored synthesis of a sphingolipid containing ceramide, a C26 VLCFA. HACD1 affinity purified from transfected HeLa cells converted 3-hydroxypalmitoyl -CoA to 2,3-trans hexadecenoyl-CoA. Other members of the HACD enzyme family, including HACD2 (PTPLB; 615939), HACD3 (PTPLAD1; 615940), and HACD4 (PTPLAD2; 615941), showed the same activity, but each had distinct affinity and rate of reaction. Coimmunoprecipitation analysis of transfected HEK293T cells revealed that HACD1 preferentially interacted with several FA condensation enzymes (see 611813), likely in an FA elongase complex.
Li et al. (2000) determined that the PTPLA gene contains 7 exons.
By genomic sequence analysis, Uwanogho et al. (1999) mapped the PTPLA gene to chromosome 10p14-p13.
Stumpf (2022) mapped the HACD1 gene to chromosome 10p12.33 based on an alignment of the HACD1 sequence (GenBank BC010353) with the genomic sequence (GRCh38).
In 4 affected members of a consanguineous Bedouin family with congenital myopathy-11 (CMYP11; 619967), Muhammad et al. (2013) identified a homozygous nonsense mutation in the HACD1 gene (Y248X; 610467.0001). The mutation was found by a combination of homozygosity mapping and whole-exome sequencing and was confirmed by Sanger sequencing. The mutation segregated with the disorder in the family and was not found in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases or in 134 healthy Bedouin controls. Skeletal muscle sample from 1 patient showed 31% residual HACD1 mRNA. Transfection studies in HEK293 cells showed that the mutation completely abrogated enzyme activity.
In a 4-year-old girl, born of consanguineous parents of Sri Lankan descent, with CMYP11, Al Amrani et al. (2020) identified a homozygous insertion in the HACD1 gene (610467.0002). The mutation, which was found by genetic testing of a multigene panel, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but the authors noted that the insertion was a long interspersed nuclear element (LINE), similar to that observed in Labrador retrievers with a form of centronuclear myopathy (see ANIMAL MODEL).
In 3 unrelated patients with CMYP11, Abbasi-Moheb et al. (2021) identified homozygous mutations in the HACD1 gene (610467.0003-610467.0005). The mutations were found by exome sequencing and confirmed by Sanger sequencing. There were 2 splice site mutations and 1 nonsense mutation. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not present in the gnomAD database. Familial segregation studies were not reported. Functional studies of the variants and studies of patient cells were not performed.
In Labrador retrievers thought to represent the first spontaneous mammalian model of autosomal recessive centronuclear myopathy (see 255200), which strikingly mimicked the clinical evolution of the human disorder, Tiret et al. (2003) mapped the disease locus to a region of canine chromosome 2 that is orthologous to human chromosome 10p. They stated that no member of the human myotubularin gene family (see, e.g., MTM1; 300415) had been mapped to this region.
Labrador retrievers affected by an autosomal recessive centronuclear myopathy (cnm) have clinical and histologic features of the human disorder. Pele et al. (2005) identified homozygosity for a centronuclear myopathy-associated insertion within PTPLA exon 2 of all affected Labrador retrievers. They identified heterozygosity for the mutation in obligate carriers. The inserted tRNA-derived short interspersed repeat element (SINE) had a striking effect on the maturation of PTPLA mRNA, whereby it could be spliced out, partially exonized, or involved in multiple exon skipping. As a result, the amount of wildtype transcripts fell to 1% in affected muscles. This example recapitulated cumulative SINE-associated transcriptional defects that have been previously described as exclusive consequences of independent mutations. Pele et al. (2005) hypothesized that impaired PTPLA signaling might be implicated in human myopathies.
Al Amrani et al. (2020) noted that, unlike human patients with HACD1 mutations, the affected dogs showed progressive clinical features and muscle biopsy findings of centronuclear myopathy.
In 4 affected members of a consanguineous Bedouin family with congenital myopathy-11 (CMYP11; 619967), Muhammad et al. (2013) identified a homozygous c.744C-A transversion (c.744C-A, NM_014241) in exon 6 of the HACD1 gene, resulting in a tyr248-to-ter (Y248X) substitution. The mutation was found by a combination of homozygosity mapping and whole-exome sequencing and was confirmed by Sanger sequencing. The mutation segregated with the disorder in the family and was not found in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases or in 134 healthy Bedouin controls. Skeletal muscle sample from 1 patient showed 31% residual HACD1 mRNA. Transfection studies in HEK293 cells showed that the mutation completely abrogated enzyme activity.
In a 4-year-old girl, born of consanguineous parents of Sri Lankan descent, with congenital myopathy-11 (CMYP11; 619967), Al Amrani et al. (2020) identified a homozygous 1.25-kb insertion in exon 6 of the HACD1 gene (c.739_740delins1250). The mutation, which was found by genetic testing of a multigene panel, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but the authors noted that the insertion was a long interspersed nuclear element (LINE), similar to that observed in Labrador retrievers with a form of centronuclear myopathy (see ANIMAL MODEL).
In an 18-year-old Iraqi woman (patient 1) with congenital myopathy-11 (CMYP11; 619967), Abbasi-Moheb et al. (2021) identified a homozygous 5-bp deletion at the boundary of exon 2 and intron 2 in the HACD1 gene (c.373_375+2delGAGGT, NM_014241.4). The mutation was predicted to result in a splicing defect, a frameshift, and premature termination (Trp87Ter). The mutation was found by exome sequencing; it was not present in the gnomAD database. The patient was lost to follow-up and no parental DNA was available for familial segregation studies. Functional studies of the variant and studies of patient cells were not performed.
In a male infant (patient 2), born of consanguineous parents from the United Arab Emirates, with congenital myopathy-11 (CMYP11; 619967), Abbasi-Moheb et al. (2021) identified a homozygous c.458G-A transition (c.458G-A, NM_014241.4) in exon 4 of the HACD1 gene, resulting in a trp153-to-ter (W153X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Familial segregation studies were not reported. Functional studies of the variant and studies of patient cells were not performed.
In an 8-year-old boy (patient 3), born of consanguineous Saudi parents, with congenital myopathy-11 (CMYP11; 619967), Abbasi-Moheb et al. (2021) identified a homozygous G-to-T transversion in intron 6 of the HACD1 gene (c.785-1G-T, NM_014241.4), predicted to result in a splicing defect. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Familial segregation studies were not reported. Functional studies of the variant and studies of patient cells were not performed.
Abbasi-Moheb, L., Westenberger, A., Alotaibi, M., Alghamdi, M. A., Hertecant, J. L., Ariamand, A., Beetz, C., Rolfs, A., Bertoli-Avella, A. M., Bauer, P. Biallelic loss-of-function HACD1 variants are a bona fide cause of congenital myopathy. Clin. Genet. 99: 513-518, 2021. [PubMed: 33354762] [Full Text: https://doi.org/10.1111/cge.13905]
Al Amrani, F., Gorodetsky, C., Hazrati, L.-N., Amburgey, K., Gonorazky, H. D., Dowling, J. J. Biallelic LINE insertion mutation in HACD1 causing congenital myopathy. Neurol. Genet. 6: e423, 2020. [PubMed: 32426512] [Full Text: https://doi.org/10.1212/NXG.0000000000000423]
Ikeda, M., Kanao, Y., Yamanaka, M., Sakuraba, H., Mizutani, Y., Igarashi, Y., Kihara, A. Characterization of four mammalian 3-hydroxyacyl-CoA dehydratases involved in very long-chain fatty acid synthesis. FEBS Lett. 582: 2435-2440, 2008. [PubMed: 18554506] [Full Text: https://doi.org/10.1016/j.febslet.2008.06.007]
Li, D., Gonzalez, O., Bachinski, L. L., Roberts, R. Human protein tyrosine phosphatase-like gene: expression profile, genomic structure, and mutation analysis in families with ARVD. Gene 256: 237-243, 2000. [PubMed: 11054553] [Full Text: https://doi.org/10.1016/s0378-1119(00)00347-4]
Muhammad, E., Reish, O., Ohno, Y., Scheetz, T., DeLuca, A., Searby, C., Regev, M., Benyamini, L., Fellig, Y., Kihara, A., Sheffield, V. C., Parvari, R. Congenital myopathy is caused by mutation of HACD1. Hum. Molec. Genet. 22: 5229-5236, 2013. [PubMed: 23933735] [Full Text: https://doi.org/10.1093/hmg/ddt380]
Pele, M., Tiret, L., Kessler, J.-L., Blot, S., Panthier, J.-J. SINE exonic insertion in the PTPLA gene leads to multiple splicing defects and segregates with the autosomal recessive centronuclear myopathy in dogs. Hum. Molec. Genet. 14: 1417-1427, 2005. Note: Erratum: Hum. Molec. Genet. 14: 1905-1906, 2005. [PubMed: 15829503] [Full Text: https://doi.org/10.1093/hmg/ddi151]
Stumpf, A. M. Personal Communication. Baltimore, Md. 07/26/2022.
Tiret, L., Blot, S., Kessler, J.-L., Gaillot, H., Breen, M., Panthier, J.-J. The cnm locus, a canine homologue of human autosomal forms of centronuclear myopathy, maps to chromosome 2. Hum. Genet. 113: 297-306, 2003. [PubMed: 12884002] [Full Text: https://doi.org/10.1007/s00439-003-0984-7]
Uwanogho, D. A., Hardcastle, Z., Balogh, P., Mirza, G., Thornburg, K. L., Ragoussis, J., Sharpe, P. T. Molecular cloning, chromosomal mapping, and developmental expression of a novel protein tyrosine phosphatase-like gene. Genomics 62: 406-416, 1999. [PubMed: 10644438] [Full Text: https://doi.org/10.1006/geno.1999.5950]