SERAC1 – Leigh syndrome

SERAC1 is a mitochondrial membrane protein involved in phosphatidylglycerol remodeling and intracellular cholesterol trafficking. Biallelic variants in SERAC1 classically cause MEGDEL syndrome, a recessive disorder featuring 3-methylglutaconic aciduria, deafness, hepatopathy, encephalopathy and Leigh-like lesions. Emerging evidence supports a direct link between SERAC1 deficiency and classical Leigh syndrome (SERAC1, Leigh syndrome).

Autosomal recessive inheritance is established by exome sequencing in a patient with Leigh syndrome who harbored a homozygous nonsense SERAC1 variant, c.202C>T (p.Arg68Ter) ([PMID:23707711]). A parallel cohort identified 15 additional unrelated MEGDEL patients with biallelic SERAC1 mutations, including recurrent LoF alleles ([PMID:22683713]), totaling 16 probands with Leigh or Leigh-like presentations.

The variant spectrum comprises primarily loss-of-function alleles: nonsense (e.g., c.202C>T (p.Arg68Ter)), splice-site (e.g., c.129-1G>C), and frameshift mutations, with a minority of missense changes (e.g., c.671A>G (p.Asp224Gly)) outside the lipase domain. The c.202C>T (p.Arg68Ter) allele recurs in multiple unrelated families ([PMID:23707711]).

Functional studies in patient fibroblasts show complete loss of SERAC1 protein by western blot and abnormal filipin staining indicating impaired cholesterol trafficking ([PMID:23707711]; [PMID:22683713]). Complementation of patient cells with wild-type SERAC1 via lentiviral infection normalizes phosphatidylglycerol subspecies ratios.

A Serac1–/– mouse model replicates key clinical and biochemical features, including mitochondrial network fragmentation, cristae disruption, respiratory chain deficiency and 3-MGA-uria. Loss of SERAC1 impairs one-carbon metabolism and induces mtDNA depletion, which is rescued by nucleoside/nucleotide supplementation in vitro and in vivo ([PMID:35235340]).

Together, genetic and experimental data provide strong evidence that SERAC1 deficiency causes Leigh syndrome under an autosomal recessive mechanism. SERAC1 should be included in diagnostic gene panels for Leigh syndrome and related mitochondrial disorders.

References

• Molecular genetics and metabolism • 2013 • Exome sequencing identifies a new mutation in SERAC1 in a patient with 3-methylglutaconic aciduria. PMID:23707711
• Nature genetics • 2012 • Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness. PMID:22683713
• Science translational medicine • 2022 • SERAC1 is a component of the mitochondrial serine transporter complex required for the maintenance of mitochondrial DNA. PMID:35235340

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