Identification of a novel splice site mutation in the SERAC1 gene responsible for the MEGDHEL syndrome

Abstract

Background MEGDHEL is an autosomal recessive syndrome defined as 3‐MEthylGlutaconic aciduria (3‐MGA) with Deafness, Hepatopathy, Encephalopathy, and Leigh‐like syndrome on magnetic resonance imaging, due to mutations in the SERAC1 (Serine Active Site Containing 1) gene, which plays a role in the mitochondrial cardiolipin metabolism. Methods We report the case of a young patient who presented with a convulsive encephalopathy, 3‐methylglutaconic aciduria, deafness, and bilateral T2 hypersignals of the putamen and the thalami, who passed away at 8 years of age. Results Analysis of nuclear genes using an ampliSeq™ targeted custom panel disclosed two compound heterozygous variants in the SERAC1 gene: a nonsense substitution in exon 4, c.202C>T, resulting in a premature stop codon (p.Arg68*), and a novel variant at a canonical splicing site upstream exon 4 (c.129‐1G>C). mRNAs sequencing from the fibroblasts of the patient showed that the splice site variant resulted in exon 3 skipping without frameshift while Western blot experiments showed the absence of SERAC1 expression compared to controls and abnormal filipin staining. Conclusion We showed that the loss of the putative transmembrane domain of SERAC1, due to a novel splice site variant, impairs the protein expression and is responsible for the MEGDHEL syndrome.

Hepatic histologic findings in a case of MEGDHEL syndrome due to SERAC1 deficiency

“…Figure 2 illustrates the mutations identified in this case in the context of the SERAC1 gene and protein with its domains. Mutations previously reported in the literature are also marked (Ling et al, 2021;Maas et al, 2017;Roeben et al, 2018;Sarig et al, 2013;Snanoudj et al, 2019). The reported pathogenic mutations span the spectrum from frameshift, nonsense, missense, splice site, extension, and deletion variants.…”

“…The intragenic deletion of exons 2-4 identified in this patient includes the start codon and thus is predicted to result in decreased expression of normal protein; whether that results from complete absence of expression, production of a truncated protein, or nonsense-mediated decay can only be confirmed with additional expression studies. Moreover, as the deletion involves the transmembrane domain, a variant protein if synthesized using an alternative initiation codon, may not localize to the speculated intracellular location et al, 2021;Maas et al, 2017;Roeben et al, 2018;Sarig et al, 2013;Snanoudj et al, 2019; NCBI reference sequence: NM_032861.4; NP_116250)…”

“…The mutations identified in this case are marked. Mutations previously reported in the literature are listed and placed alongside based on location, and colored if in the lipase or transmembrane domain (Ling et al, 2021; Maas et al, 2017; Roeben et al, 2018; Sarig et al, 2013; Snanoudj et al, 2019; NCBI reference sequence: NM_032861.4; NP_116250)…”

Complicated Hereditary Spastic Paraplegia Caused by SERAC1 Variants in a Chinese Family

“…Previous studies have identified a causal relationship between SERAC1 variants and MEGDEL syndrome (11)(12)(13)(14)(15). Approximately 70 cases of MEGDEL syndrome have been reported worldwide according to a report in 2020 (15).…”

Mitochondria-Associated Membrane Scaffolding with Endoplasmic Reticulum: A Dynamic Pathway of Developmental Disease

“…Abnormal function can increase the ratio of phosphatidylglycerol-34:1 to phosphatidylglycerol-36:1 and decrease the level of mono-acyl-glycerol (bis) phosphate and subsequently altering the accumulation of cholesterol ( Wortmann et al, 2012 ). Recently, SERAC1 pathological variants were also found to change acyl-chain composition of PG, a precursor of cardiolipin, giving rise to normal levels of cardiolipin but possessing altered acyl chain composition ( Snanoudj et al, 2019 ).…”