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Case Reports
. 2021 Sep 29;16(1):403.
doi: 10.1186/s13023-021-02028-4.

Identification and functional analysis of novel SLC25A19 variants causing thiamine metabolism dysfunction syndrome 4

Yuanying Chen #  1   2 , Boliang Fang #  3 , Xuyun Hu  1   2 , Ruolan Guo  1   2 , Jun Guo  1   2 , Kenan Fang  4 , Jingwen Ni  4 , Wei Li  1   2 , Suyun Qian  5 , Chanjuan Hao  6   7
Affiliations
Case Reports

Identification and functional analysis of novel SLC25A19 variants causing thiamine metabolism dysfunction syndrome 4

Yuanying Chen et al. Orphanet J Rare Dis. .

Abstract

Background: Thiamine metabolism dysfunction syndrome 4 (THMD4, OMIM #613710) is an autosomal recessive inherited disease caused by the deficiency of SLC25A19 that encodes the mitochondrial thiamine pyrophosphate (TPP) transporter. This disorder is characterized by bilateral striatal degradation and progressive polyneuropathy with the onset of fever of unknown origin. The limited number of reported cases and lack of functional annotation of related gene variants continue to limit diagnosis.

Results: We report three cases of encephalopathy from two unrelated pedigrees with basal ganglia signal changes after fever of unknown origin. To distinguish this from other types of encephalopathy, such as acute necrotizing encephalopathy, exome sequencing was performed, and four novel heterozygous variations, namely, c.169G>A (p.Ala57Thr), c.383C>T (p.Ala128Val), c.76G>A (p.Gly26Arg), and c.745T>A (p.Phe249Ile), were identified in SLC25A19. All variants were confirmed using Sanger sequencing. To determine the pathogenicity of these variants, functional studies were performed. We found that mitochondrial TPP levels were significantly decreased in the presence of SLC25A19 variants, indicating that TPP transport activities of mutated SLC25A19 proteins were impaired. Thus, combining clinical phenotype, genetic analysis, and functional studies, these variants were deemed as likely pathogenic.

Conclusions: Exome sequencing analysis enables molecular diagnosis as well as provides potential etiology. Further studies will enable the elucidation of SLC25A19 protein function. Our investigation supplied key molecular evidence for the precise diagnosis of and clinical decision-making for a rare disease.

Keywords: Compound heterozygosity; Exome sequencing; Functional study; SLC25A19; Thiamine metabolism dysfunction syndrome 4; Thiamine pyrophosphate.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Brain magnetic resonance imaging (MRI) of the three patients. a Brain MRI of Patient 1 showing abnormal signals in the bilateral basal ganglia, thalamus margin, hippocampus, midline frontal lobe, and temporal cortex. b Brain MRI of Patient 2 displaying abnormalities in the bilateral basal ganglia, thalamus margin, and brainstem. c Brain MRI of Patient 3 showing signal changes in basal ganglia and thalamus edge
Fig. 2
Fig. 2
Pedigree and Sanger sequencing of the patients. Pedigree and Sanger sequencing results of Patient 1 (a, b) and Patients 2 and 3 (c, d)
Fig. 3
Fig. 3
Sequence alignment and predicted topology of SLC25A19. a Sequence alignment of SLC25A19 among species. b Predicted topology of SLC25A19 using Phyre2. The circles represent amino acids of SLC25A19, and the variants identified in this study are labeled as red, blue, green, and yellow
Fig. 4
Fig. 4
Protein expression and thiamine pyrophosphate (TPP) levels in HEK 293 cells. Protein expression levels of Flag-SLC25A19 and its mutants (a, b). TPP levels in the mitochondrial fraction and post-mitochondrial supernatant when overexpressed Flag-SLC25A19 and its mutants in HEK 293 cells (c, d)
See this image and copyright information in PMC

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