HGNC Approved Gene Symbol: SERAC1
SNOMEDCT: 711409002;
Cytogenetic location: 6q25.3 Genomic coordinates (GRCh38) : 6:158,109,519-158,168,262 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q25.3 | 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome | 614739 | Autosomal recessive | 3 |
SERAC1 functions in phosphatidylglycerol remodeling that is essential for mitochondrial function and intracellular cholesterol trafficking (Wortmann et al., 2012).
Wortmann et al. (2012) reported that the deduced SERAC1 protein has an N-terminal signal sequence and a C-terminal serine-lipase/esterase domain containing the consensus lipase motif GxSxG. Quantitative PCR analysis detected variable SERAC1 expression in all adult and fetal tissues examined, with highest expression in fetal skeletal muscle, followed by adult brain, fetal heart, and fetal kidney. Expression in fetal brain was much lower than that in adult brain. SERAC1 was detected in all specific adult brain regions examined, with highest expression in occipital cortex, followed by frontal cortex, cerebellum, and hippocampus. Western blot analysis of fractionated human fibroblasts and immunohistochemical analysis showed SERAC1 localization in both mitochondria and endoplasmic reticulum in a pattern consistent with enrichment in the mitochondria-associated membranes. Database analysis identified SERAC1 orthologs in all eukaryotes examined, with highest conservation in the lipase domain.
Wortmann et al. (2012) assayed control fibroblasts and fibroblasts from patients with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; 614739) due to SERAC1 mutations and transfected patient fibroblasts with wildtype SERAC1. The results showed that SERAC1 functions in the transacylation-acylation reaction that converts phosphatidylglycerol-34:1 to phosphatidylglycerol-36:1.
Wortmann et al. (2012) determined that the SERAC1 gene contains 17 exons and spans about 59 kb.
Hartz (2012) mapped the SERAC1 gene to chromosome 6q25.3 based on an alignment of the SERAC1 sequence (GenBank AK027823) with the genomic sequence (GRCh37).
In 15 individuals from 13 families with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; 614739), which is also referred to as 3-methylglutaconic aciduria type VI (MGCA6), Wortmann et al. (2012) identified 14 different homozygous or compound heterozygous mutations in the SERAC1 gene (see, e.g., 614725.0001-614725.0005). The first 2 mutations were identified by exome sequencing and confirmed by Sanger sequencing. The patients had psychomotor retardation, spasticity and/or dystonia, deafness, and brain lesions on MRI. Laboratory studies showed increased serum lactate and alanine, urinary 3-MGA, mitochondrial oxidative phosphorylation defects, abnormal mitochondria, an abnormal phosphatidylglycerol and cardiolipin spectrum in fibroblasts, and abnormal accumulation of unesterified cholesterol within cells.
In a patient with MEGDEL, Tort et al. (2013) identified a homozygous truncating mutation in the SERAC1 gene (R68X; 614725.0006). The mutation was found by exome sequencing and segregated with the disorder in the family.
Among 67 patients with MEGDEL, including 39 previously unreported individuals, Maas et al. (2017) identified 41 SERAC1 sequence variants, including 20 novel variants. (Maas et al. (2017) used the acronym MEGDHEL to include the clinical feature of hepatopathy.) The mutations were located throughout the gene, with no hotspots, although there were several recurrent mutations, suggesting founder effects in certain populations. Most of the mutations were predicted to result in a loss of function, suggesting that missense mutations may be better tolerated.
In 2 unrelated Indian patients, born to consanguineous parents, with MEGDEL, Rama Devi and Lingappa (2018) identified homozygous mutations in the SERAC1 gene (614725.0008 and 614725.0009). The mutations were found by whole-exome sequencing. In 1 family, the parents were confirmed by Sanger sequencing to be carriers; in the other family, the parents refused to be sequenced.
In a Saudi Arabian boy with MEGDEL, Lumish et al. (2014) identified compound heterozygous mutations in the SERAC1 gene (614725.0001 and 614725.0010). The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. The father carried one of the mutations; the mother's status was not given.
In 3 members of a consanguineous Turkish family with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; 614739), Wortmann et al. (2012) identified a homozygous 442C-T transition in the SERAC1 gene, resulting in an arg148-to-ter (R148X) substitution. The mutation was identified by exome sequencing and confirmed by Sanger sequencing, and was not found in 369 controls. The index patient had previously been reported as patient 3 by Wortmann et al. (2006). Clinical features included psychomotor retardation, recurrent infections in infancy, hypoglycemia, spasticity, dystonia, sensorineural deafness, brain atrophy, and lesions on brain imaging. Laboratory studies showed increased serum lactate and alanine, urinary 3-MGA, mitochondrial oxidative phosphorylation defects, abnormal mitochondria, an abnormal phosphatidylglycerol and cardiolipin spectrum in fibroblasts, and abnormal accumulation of unesterified cholesterol within cells.
In a Saudi Arabian patient with MEGDEL, Lumish et al. (2014) identified compound heterozygous mutations in the SERAC1 gene: R148X and a 1-bp deletion (c.438delC; 614725.0010) in the SERAC1 gene, predicted to result in a frameshift and premature termination (Thr147fsTer22). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The patient's father was shown to be a carrier of the c.438delC mutation. The c.438delC mutation was not present in the 1000 Genomes Project and EVS databases.
In 2 unrelated patients with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; 614739), Wortmann et al. (2012) identified a homozygous G-to-C transversion in the donor splice site of exon 13 of the SERAC1 gene (1403+1G-C), resulting in the skipping of exon 13 and nonsense-mediated mRNA decay. One patient was born of consanguineous Pakistani parents and the other of unrelated Indian parents; haplotype analysis suggested a founder effect. The mutation was not found in 369 controls. The patients had psychomotor retardation, spasticity, dystonia, Leigh syndrome-like lesions on brain imaging, and increased urinary 3-MGA. Only 1 had hearing loss.
In a Turkish girl, born of consanguineous parents, with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; 614739), Wortmann et al. (2012) identified a homozygous 4-bp deletion (1167delTCAG) in a canonical splice site of the SERAC1 gene, resulting in the skipping of exon 12 and nonsense-mediated mRNA decay. The mutation was not found in 369 controls. The patient, who was originally reported as patient 1 by Wortmann et al. (2006), had recurrent infections, failure to thrive, mental retardation, spasticity and extrapyramidal symptoms, deafness, hypoglycemia, increased serum lactate, abnormal lesions on brain imaging, and oxidative phosphorylation defects.
In a Turkish girl, born of consanguineous parents, with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; 614739), Wortmann et al. (2012) identified a homozygous 3-bp deletion (1435delCTT) in the SERAC1 gene, resulting in an in-frame deletion of an amino acid in the highly conserved lipase domain. The patient was originally reported as patient 4 by Wortmann et al. (2006). The mutation was not found in 369 controls.
In a Dutch girl with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; 614739), Wortmann et al. (2012) identified a homozygous 2-bp duplication (1627dupTC) in the SERAC1 gene, resulting in a frameshift and premature termination (Val544LeufsTer43). The patient was originally reported as patient 2 by Wortmann et al. (2006). The mutation was not found in 369 controls.
In a patient with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; 614739), Tort et al. (2013) identified a homozygous c.202C-T transition in the SERAC1 gene, resulting in an arg68-to-ter (R68X) substitution. Western blot of patient cells showed no detectable SERAC1 protein. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.
In 6 members of a large consanguineous Iraqi family with a mild variant of 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; 614739), Roeben et al. (2018) identified a homozygous T-to-C transition (c.91+6T-C, NM_032861.3) close to the canonical splice donor of exon 2 in the SERAC1 gene, which is the first coding exon in the transcript. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP (build 142), 1000 Genomes Project, or ExAC (February 2016) databases, or in 8,000 in-house exomes. Analysis of patient cells showed 2 shortened mutant SERAC1 transcripts lacking exon 2 and exons 2 and 3, respectively. There was no suggestion of mRNA decay, but Western blot analysis detected no full-length SERAC1 protein. Patient cells showed impaired phosphatidylglycerol remodeling, although the changes were milder than that observed in other patients with MEGDEL. Correspondingly, the patients presented with juvenile-onset progressive spastic paraplegia and mild cognitive impairment, although none had deafness. The findings expanded the phenotypic spectrum associated with SERAC1 mutations.
In an Indian patient, born to consanguineous parents, with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; 614739), Rama Devi and Lingappa (2018) identified homozygosity for a 4-bp duplication (c.1643_1646dupATCT, NM_032861.3) in exon 15 of the SERAC1 gene, predicted to result in a frameshift and premature termination (Leu550fsTer19). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The mutation was not present in the 1000 Genomes Project database and was present in the ExAC database at a minor allele frequency of 0.02%. The patient had a history of neonatal hepatopathy and metabolic acidosis, developmental delay, and dystonia. Urine organic acid analysis in the patient showed elevations of 3-methylglutaconic and 3-methylglutaric acids.
In an 11-year-old Indian patient, born of consanguineous parents, with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; 614739), Rama Devi and Lingappa (2018) identified homozygosity for a c.1709G-A transition (c.1709G-A, NM_032861.3) in exon 15 of the SERAC1 gene, resulting in a gly526-to-glu (G526E) substitution. The mutation was identified by whole-exome sequencing. The mutation was not present in the 1000 Genomes Project and ExAC databases. The patient had a history of developmental regression, ataxia, jaundice, and basal ganglia abnormalities on MRI. Urine organic acid analysis in the patient showed mild elevations of 3-methylglutaconic and 3-methylglutaric acids.
For description of the 1-bp deletion (c.438delC) in the SERAC1 gene, predicted to result in a frameshift and premature termination (Thr147fsTer22), that was found in compound heterozygous state in a patient with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; 614739) by Lumish et al. (2014), see 614725.0001.
Hartz, P. A. Personal Communication. Baltimore, Md. 7/17/2012.
Lumish, H. S., Yang, Y., Xia, F., Wilson, A., Chung, W. K. The expanding MEGDEL phenotype: optic nerve atrophy, microcephaly, and myoclonic epilepsy in a child with SERAC1 mutations. JIMD Rep. 16: 75-79, 2014. [PubMed: 24997715] [Full Text: https://doi.org/10.1007/8904_2014_322]
Maas, R. R., Iwanicka-Pronicka, K., Kalkan Ucar, S., Alhaddad, B., AlSayed, M., Al-Owain, M. A., Al-Zaidan, H. I., Balasubramaniam, S., Baric, I., Bubshait, D. K., Burlina, A., Christodoulou, J., and 46 others. Progressive deafness-dystonia due to SERAC1 mutations: a study of 67 cases. Ann. Neurol. 82: 1004-1015, 2017. [PubMed: 29205472] [Full Text: https://doi.org/10.1002/ana.25110]
Rama Devi, A. R., Lingappa, L. Novel mutations in SERAC1 gene in two Indian patients presenting with dystonia and intellectual disability. Europ. J. Med. Genet. 61: 100-103, 2018. [PubMed: 28778788] [Full Text: https://doi.org/10.1016/j.ejmg.2017.07.013]
Roeben, B., Schule, R., Ruf, S., Bender, B., Alhaddad, B., Benkert, T., Meitinger, T., Reich, S., Bohringer, J., Langhans, C.-D., Vaz, F. M., Wortmann, S. B., Marquart, T., Haack, T. B., Krageloh-Mann, I., Schols, L., Synofzik, M. SERAC1 deficiency causes complicated HSP: evidence from a novel splice mutation in a large family. J. Med. Genet. 55: 39-47, 2018. [PubMed: 28916646] [Full Text: https://doi.org/10.1136/jmedgenet-2017-104622]
Tort, F., Garcia-Silva, M. T., Ferrer-Cortes, X., Navarro-Sastre, A., Garcia-Villoria, J., Coll, M. J., Vidal, E., Jimenez-Almazan, J., Dopazo, J., Briones, P., Elpeleg, O., Ribes, A. Exome sequencing identifies a new mutation in SERAC1 in a patient with 3-methylglutaconic aciduria. Molec. Genet. Metab. 110: 73-77, 2013. [PubMed: 23707711] [Full Text: https://doi.org/10.1016/j.ymgme.2013.04.021]
Wortmann, S. B., Vaz, F. M., Gardeitchik, T., Vissers, L. E. L. M., Renkema, G. H., Schuurs-Hoeijmakers, J. H. M., Kulik, W., Lammens, M., Christin, C., Kluijtmans, L. A. J., Rodenburg, R. J., Nijtmans, L. G. J., and 22 others. Mutations in the phospholipid remodeling gene SERCA1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness. Nature Genet. 44: 797-802, 2012. [PubMed: 22683713] [Full Text: https://doi.org/10.1038/ng.2325]
Wortmann, S., Rodenburg, R. J. T., Huizing, M., Loupatty, F. J., de Koning, T., Kluijtmans, L. A. J., Engelke, U., Wevers, R., Smeitink, J. A. M., Morava, E. Association of 3-methylglutaconic aciduria with sensori-neural deafness, encephalopathy, and Leigh-like syndrome (MEGDEL association) in four patients with a disorder of the oxidative phosphorylation. Molec. Genet. Metab. 88: 47-52, 2006. [PubMed: 16527507] [Full Text: https://doi.org/10.1016/j.ymgme.2006.01.013]