Alternative titles; symbols
HGNC Approved Gene Symbol: ABHD16A
Cytogenetic location: 6p21.33 Genomic coordinates (GRCh38): 6:31,686,955-31,703,324 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.33 | Spastic paraplegia 86, autosomal recessive | 619735 | Autosomal recessive | 3 |
The ABHD16A gene is member of the alpha/beta hydrolase domain-containing protein family that participates in lipid metabolism and intracellular signaling. The ABHD16A enzyme is the main brain phosphatidylserine (PS) hydrolase (summary by Yahia et al., 2021).
Using linkage data and cosmid cloning to identify genes in a region centromeric to HLA-B (142830) in the major histocompatibility complex in JY human B-lymphoblastoid cells, Spies et al. (1989) identified GPANK1 (142610) and ABHD16A, which they called BAT4 and BAT5, respectively. Northern blot analysis detected weak BAT5 expression at 2.0 kb in all 5 human cell lines examined.
Yahia et al. (2021) noted that the ABHD16A gene encodes 2 transcripts with 558 and 525 amino acids, respectively. The longer is highly expressed in brain, muscles, testis, and heart, whereas the shorter is expressed mainly in testis and minimally in brain. Abhd16a has a heterogeneous expression in the murine brain and is enriched in the cerebellum. It is an integral endoplasmic reticulum protein with a cytosolic-oriented active site.
Yahia et al. (2021) stated that the ABHD16A gene contains 21 exons.
Using linkage data and cosmid cloning, Spies et al. (1989) mapped the BAT4 and BAT5 genes near the TNF (191160)-TNFB (LTA; 153440) gene cluster on chromosome 6p21.3.
In the endoplasmic reticulum, ABHD16A colocalizes with ABHD12 (613599), the principle brain lysophosphatidylserine (lyso-PS) hydrolase. These 2 enzymes are the main enzymes responsible for brain lyso-PS metabolism: ABHD16A generates lyso-PS from PS substrates, and ABHD12 catabolizes them into fatty acids and phosphoserine (summary by Yahia et al., 2021).
ABHD16A, the major phosphatidylserine in the brain, converts PS to lyso-PS, which is a signaling lipid abundant in the central nervous system and immune cells, where it is postulated to regulate numerous processes (summary by Lemire et al., 2021).
In 4 patients from 2 unrelated consanguineous Sudanese families with autosomal recessive spastic paraplegia-86 (SPG86; 619735), Yahia et al. (2021) identified homozygous loss-of-function mutations in the ABHD16A gene (142620.0001 and 142620.0002). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Patient fibroblasts showed lack of ABHD16A expression. The levels of PS substrates were increased, and the levels of lyso-PS were decreased compared to controls, suggesting that the variants caused a loss of ABHD16A enzyme function. Yahia et al. (2021) hypothesized that low levels of lyso-PS, which participates in cellular signaling and neuronal growth, could contribute to the neurologic dysfunction in the brain. The pathogenic mechanism may also be related to altered PS metabolism.
In 11 patients from 6 unrelated families with SPG86, Lemire et al. (2021) identified homozygous or compound heterozygous mutations in the ABHD16A gene (see, e.g., 142620.0003-142620.0005). The mutations were found by exome sequencing; the families were ascertained through collaborative efforts. The mutations segregated with the disorder in all families. There were 4 missense, 1 nonsense, and 1 frameshift mutation, which were located throughout the gene. Immunoblot analysis of patient fibroblasts showed little to no ABHD16A protein compared to controls. These cells showed a broad range of proliferation compared to controls. Lipidomic studies in patient fibroblasts and plasma showed increased PS levels, but did not show a clear change in lyso-PS levels compared to controls. However, other lipidomic changes were observed. The authors noted that lipidomic changes may be different in neuronal cells, which were not studied. The findings demonstrated the critical role of lipid metabolism and homeostasis in maintaining the nervous system.
In 2 sibs, born of unrelated Chilean parents, with autosomal recessive SPG86, Miyake et al. (2022) identified a homozygous nonsense mutation in the ABHD16A gene (142620.0006). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function. The authors noted that the gene is expressed in various human tissues which can explain the complex phenotype.
In 2 brothers, born of consanguineous Sudanese parents (family F37), with autosomal recessive spastic paraplegia-86 (SPG86; 619735), Yahia et al. (2021) identified a homozygous c.340C-T transition (c.340C-T, NM_021160.2) in the ABHD16A gene, resulting in an arg114-to-ter (R114X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not present in the gnomAD database. Patient fibroblasts showed absence of the ABHD16A protein and evidence of decreased enzyme activity, consistent with a loss of function.
In 2 sibs, born of consanguineous Sudanese parents (family F69), with autosomal recessive spastic paraplegia-86 (SPG86; 619735), Yahia et al. (2021) identified a homozygous c.1370G-A transition (c.1370G-A, NM_021160.2) in the ABHD16A gene, resulting in an arg457-to-gln (R457Q) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was present once in the heterozygous state in the gnomAD database (4 x 10(-6)). In silico analysis suggested that the variant may alter splicing. Patient fibroblasts showed absence of the ABHD16A protein and evidence of decreased enzyme activity, consistent with a loss of function.
In 4 patients from 2 unrelated French Canadian families (families 1 and 2) with autosomal recessive spastic paraplegia-86 (SPG86; 619735), Lemire et al. (2021) identified a homozygous c.353G-A transition (c.353G-A, NM_021160.2) in the ABHD16A gene, resulting in an arg118-to-his (R118H) substitution at a highly conserved residue. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. It was found twice in the gnomAD database (frequency of 0.0008). Haplotype analysis suggested a founder effect. Immunoblot analysis of patient fibroblasts showed little to no ABHD16A protein, consistent with a loss of function.
In 2 sibs, born of consanguineous Armenian parents (family 3), with autosomal recessive spastic paraplegia-86 (SPG86; 619735), Lemire et al. (2021) identified a homozygous c.1226T-G transversion (c.1226T-G, NM_021160.2) in the ABHD16A gene, resulting in a leu409-to-arg (L409R) substitution at a highly conserved residue. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
In 2 sisters, born of consanguineous Egyptian parents (family 5), with autosomal recessive spastic paraplegia-86 (SPG86; 619735), Lemire et al. (2021) identified a homozygous c.362A-T transversion (c.362A-T, NM_021160.2) in the ABHD16A gene, resulting in an asn121-to-ile (N121I) substitution. The mutation, which was found by exome sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Immunoblot analysis of patient fibroblasts showed little to no ABHD16A protein, consistent with a loss of function.
In 2 sibs, born of unrelated Chilean parents, with autosomal recessive spastic paraplegia-86 (SPG86; 619735), Miyake et al. (2022) identified a homozygous c.835C-T transition (c.835C-T, NM_021160) in exon 9 of the ABHD16A gene, resulting in a gln279-to-ter (Q279X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function. The authors noted that the gene is expressed in various human tissues, which can explain the complex phenotype.
Lemire, G., Ito, Y. A., Marshall, A. E., Chrestian, N., Stanley, V., Brady, L., Tarnopolsky, M., Curry, C. J., Hartley, T., Mears, W., Derksen, A., Rioux, N., and 12 others. ABHD16A deficiency causes a complicated form of hereditary spastic paraplegia associated with intellectual disability and cerebral anomalies. Am. J. Hum. Genet. 108: 2017-2023, 2021. [PubMed: 34587489] [Full Text: https://doi.org/10.1016/j.ajhg.2021.09.005]
Miyake, N., Silva, S., Troncoso, M., Okamoto, N., Andachi, Y., Kato, M., Iwabuchi, C., Hirose, M., Fujita, A., Uchiyama, Y., Matsumoto, N. A homozygous ABHD16A variant causes a complex hereditary spastic paraplegia with developmental delay, absent speech, and characteristic face. Clin. Genet. 101: 359-363, 2022. [PubMed: 34866177] [Full Text: https://doi.org/10.1111/cge.14097]
Spies, T., Blanck, G., Bresnahan, M., Sands, J., Strominger, J. L. A new cluster of genes within the human major histocompatibility complex. Science 243: 214-217, 1989. [PubMed: 2911734] [Full Text: https://doi.org/10.1126/science.2911734]
Yahia, A., Elsayed, L. E. O., Valter, R., Hamed, A. A. A., Mohammed, I. N., Elseed, M. A., Salih, M. A., Esteves, T., Auger, N., Abubaker, R., Koko, M., Abozar, F., and 17 others. Pathogenic variants in ABHD16A cause a novel psychomotor developmental disorder with spastic paraplegia. Front. Neurol. 12: 720201, 2021. [PubMed: 34489854] [Full Text: https://doi.org/10.3389/fneur.2021.720201]