Alternative titles; symbols
HGNC Approved Gene Symbol: DDHD1
SNOMEDCT: 763376002;
Cytogenetic location: 14q22.1 Genomic coordinates (GRCh38): 14:53,036,755-53,153,323 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q22.1 | Spastic paraplegia 28, autosomal recessive | 609340 | Autosomal recessive | 3 |
Phosphatidic acid is released following cell activation and functions as a second messenger in several signaling pathways. DDHD1 is a lipase that catalyzes degradation of phosphatidic acid and attenuates cell activation (Higgs et al., 1998).
Higgs et al. (1998) cloned Papla1 from a bovine testis cDNA library. The deduced 875-amino acid protein contains a putative active-site serine embedded in a conserved lipase motif (GxSxG), as well as a possible coiled-coil region. Northern blot analysis of human tissues revealed variable expression of 5 PAPLA1 transcripts of 2.8 to over 10 kb.
By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2000) cloned DDHD1, which they designated KIAA1705. The deduced 498-amino acid protein shares similarity with a putative human phospholipase (SEC23IP). RT-PCR ELISA detected moderate to high DDHD1 expression in all adult and fetal tissues and adult brain regions examined. Highest expression was in adult brain.
Tesson et al. (2012) found expression of the Ddhd1 gene in the developing mouse brain, but not in peripheral tissues. Ddhd1 was found diffusely in the cytosol, with some mitochondrial localization.
Higgs et al. (1998) found that expression of bovine Papla1 in COS-1 cells increased the basal phospholipase activity against phosphatidic acid. Mutation of the active-site serine abrogated this activity.
Ma et al. (2007) found that DHD1 expression negatively correlated with plasma high density lipoprotein levels in leukocytes from normal humans.
Hartz (2012) mapped the DDHD1 gene to chromosome 14q22.1 based on an alignment of the DDHD1 sequence (GenBank AB051492) with the genomic sequence (GRCh37).
In 3 affected members of a consanguineous Moroccan family with autosomal recessive spastic paraplegia-28 (SPG28; 609340) originally reported by Bouslam et al. (2005), Tesson et al. (2012) identified a homozygous mutation in the DDHD1 gene (614603.0001). The mutation, which was identified by exome sequencing of the candidate region and confirmed by Sanger sequencing, was not present in several large control databases. Biallelic mutations in the DDHD1 gene (614603.0002-614603.0004) were identified in affected individuals from 2 additional families with a similar phenotype. In the same study, Tesson et al. (2012) identified pathogenic mutations in the CYP2U1 gene (610670) as a cause of SPG56 (615030). Both the DDHD1 and CYP2U1 gene products were expressed concomitantly in the developing mouse brain, and both showed partial mitochondrial localization. Mutant cells from SPG28 and SPG56 patients showed significantly lower mitochondrial respiration activity, lower ATP levels, and increased cytosolic hydrogen peroxide compared to controls. However, isolated catalytic activities of each of the respiratory chain complexes, measured after disruption of the mitochondrial membrane, were similar to controls. SPG56 fibroblasts showed structural abnormalities, suggesting a defect in mitochondrial membrane organization. Loss of DDHD1 function could result in reduced phospholipase A1 activity, causing increased phospholipid in the mitochondrial membrane that may disrupt its function. DDHD1 also works in the endoplasmic reticulum to form lipid messengers; these phospholipids and fatty acids can serve as precursors of a variety of lipid messengers and thus affect signaling of hormones or neurotransmitters. In addition, accumulation of reactive oxygen species may contribute to neurodegeneration. The study indicated that both DDHD1 and CYP2U1 are involved in the same pathway related to lipid metabolism and disruption of mitochondrial function, suggesting a common disease pathway in SPG.
In 3 affected members of a consanguineous Moroccan family with autosomal recessive spastic paraplegia-28 (SPG28; 609340) originally reported by Bouslam et al. (2005), Tesson et al. (2012) identified a homozygous 1766G-A transition in the last nucleotide of exon 6 of the DDHD1 gene. The mutation, which was identified by exome sequencing of the candidate region and confirmed by Sanger sequencing, was not present in several large control databases. Transcript analysis of patient cells showed that the 1766G-A mutation resulted in aberrant splicing and introduction of a premature stop codon. The patients had pure spastic paraplegia with distal sensory loss in the lower limbs and mild upper limb involvement. Age at onset ranged from 6 to 15 years, and the disorder was slowly progressive. The patient with earliest onset also had pes cavus and scoliosis.
In 2 Turkish brothers, born of consanguineous parents, with autosomal recessive spastic paraplegia-28 (SPG28; 609340), Tesson et al. (2012) identified a homozygous 1-bp deletion (1874delT) in exon 10 of the DDHD1 gene, resulting in a frameshift and premature termination (Leu625Ter). Each unaffected parent was heterozygous for 1 of the mutations. The brothers developed progressive spastic gait beginning in adolescence. One had a cerebellar oculomotor disturbance with saccadic eye pursuit.
In a 62-year-old French woman with autosomal recessive spastic paraplegia-28 (SPG28; 609340), Tesson et al. (2012) identified compound heterozygosity for 2 mutations in the DDHD1 gene: a 1249C-T transition in exon 4, resulting in a gln417-to-ter (Q417X) substitution, and a G-to-T transversion in intron 11 (2438-1G-T; 614603.0004), resulting in a splice site mutation. She had had spastic paraplegia since infancy and also had axonal neuropathy.
For discussion of the splice site mutation in the DDHD1 gene (2438-1G-T) that was found in compound heterozygous state in a patient with autosomal recessive spastic paraplegia-28 (SPG28; 609340) by Tesson et al. (2012), see 614603.0003.
Bouslam, N., Benomar, A., Azzedine, H., Bouhouche, A., Namekawa, M., Klebe, S., Charon, C., Durr, A., Ruberg, M., Brice, A., Yahyaoui, M., Stevanin, G. Mapping of a new form of pure autosomal recessive spastic paraplegia (SPG28). Ann. Neurol. 57: 567-571, 2005. [PubMed: 15786464] [Full Text: https://doi.org/10.1002/ana.20416]
Hartz, P. A. Personal Communication. Baltimore, Md. 4/25/2012.
Higgs, H. N., Han, M. H., Johnson, G. E., Glomset, J. A. Cloning of a phosphatidic acid-preferring phospholipase A1 from bovine testis. J. Biol. Chem. 273: 5466-5477, 1998.
Ma, J., Dempsey, A. A., Stamatiou, D., Marshall, K. W., Liew, C.-C. Identifying leukocyte gene expression patterns associated with plasma lipid levels in human subjects. Atherosclerosis 191: 63-72, 2007. [PubMed: 16806233] [Full Text: https://doi.org/10.1016/j.atherosclerosis.2006.05.032]
Nagase, T., Kikuno, R., Hattori, A., Kondo, Y., Okumura, K., Ohara, O. Prediction of the coding sequences of unidentified human genes. XIX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 347-355, 2000. [PubMed: 11214970] [Full Text: https://doi.org/10.1093/dnares/7.6.347]
Tesson, C., Nawara, M., Salih, M. A. M., Rossignol, R., Zaki, M. S., Al Balwi, M., Schule, R., Mignot, C., Obre, E., Bouhouche, A., Santorelli, F. M., Durand, C. M., and 30 others. Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia. Am. J. Hum. Genet. 91: 1051-1064, 2012. [PubMed: 23176821] [Full Text: https://doi.org/10.1016/j.ajhg.2012.11.001]