Uridine Treatment of the First Known Case of SLC25A36 Deficiency

Abstract

SLC25A36 is a pyrimidine nucleotide carrier playing an important role in maintaining mitochondrial biogenesis. Deficiencies in SLC25A36 in mouse embryonic stem cells have been associated with mtDNA depletion as well as mitochondrial dysfunction. In human beings, diseases triggered by SLC25A36 mutations have not been described yet. We report the first known case of SLC25A36 deficiency in a 12-year-old patient with hypothyroidism, hyperinsulinism, hyperammonemia, chronical obstipation, short stature, along with language and general developmental delay. Whole exome analysis identified the homozygous mutation c.803dupT, p.Ser269llefs*35 in the SLC25A36 gene. Functional analysis of mutant SLC25A36 protein in proteoliposomes showed a virtually abolished transport activity. Immunoblotting results suggest that the mutant SLC25A36 protein in the patient undergoes fast degradation. Supplementation with oral uridine led to an improvement of thyroid function and obstipation, increase of growth and developmental progress. Our findings suggest an important role of SLC25A36 in hormonal regulations and oral uridine as a safe and effective treatment.

Hyperinsulinism/hyperammonemia syndrome caused by biallelic SLC25A36 mutation

“…We demonstrate that HI/HA syndrome, known to be caused by gain of function mutations in GLUD1 , may also be caused by a biallelic mutation in SLC25A36 , confirming two recent independent publications 8,9 . SLC25A36 encodes a member of the nuclear‐encoded solute carrier 25 (SLC25) family, also known as the mitochondrial carrier family (MCF).…”

“…Through linkage analysis, whole‐exome sequencing (WES), and segregation analysis, a homozygous SLC25A36 mutation was identified at the splicing canonical donor site between exons 3–4, resulting in skipping of exon 3. Our results are in line with the two recent independent studies, demonstrating SLC25A36 mutations causing HI/HA syndrome 8,9 . We clearly delineate the disease phenotype and summarize the seven cases known to date.…”

“…Importantly, the chronic constipation, hypothyroidism, as well as language and developmental delay described in the Turkish patient, 8 were not found in our four patients or in the two previously reported patients of Palestinian ancestry 9 . This suggests that they are either due to other causes and not part of the disease phenotype, or represent phenotypic variability stemming from different SLC25A36 mutations.…”

Mitochondrial transport and metabolism of the major methyl donor and versatile cofactor S‐adenosylmethionine, and related diseases: A review†

“…The second approach using the EPRA method provides a quantitative measure of the mutation effect on the transport capacity and has been employed to assess the effects of many disease-causing mutations in other MCs. [128][129][130][131][132][133][134][135][136][137][138][139] The recombinantly expressed SLC25A26 mutants p.Ala102Val, p.Pro199Leu and the truncated variant displayed virtually abolished transport activity, whereas p.Val148Gly was about 15% active compared with the wild-type protein. 127 The results of the first and second approaches are therefore fairly well in agreement.…”

“…It was also shown that the latter variant was not targeted to mitochondria. The second approach using the EPRA method provides a quantitative measure of the mutation effect on the transport capacity and has been employed to assess the effects of many disease‐causing mutations in other MCs 128–139 . The recombinantly expressed SLC25A26 mutants p.Ala102Val, p.Pro199Leu and the truncated variant displayed virtually abolished transport activity, whereas p.Val148Gly was about 15% active compared with the wild‐type protein 127 .…”