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SOLUTE CARRIER FAMILY 25, MEMBER 42; SLC25A42

SOLUTE CARRIER FAMILY 25, MEMBER 42; SLC25A42

HGNC Approved Gene Symbol: SLC25A42Cytogenetic location: 19p13.11 Genomic coordinates (GRCh38): 19:19,063,993-19,113,029 (from NCBI)▼ DescriptionSLC25A42 bel...

HGNC Approved Gene Symbol: SLC25A42

Cytogenetic location: 19p13.11 Genomic coordinates (GRCh38): 19:19,063,993-19,113,029 (from NCBI)

▼ Description
SLC25A42 belongs to the SLC25 family of mitochondrial carrier proteins (Haitina et al., 2006). SLC25A42 is a mitochondrial coenzyme A (CoA) transporter (summary by Shamseldin et al., 2016).

▼ Cloning and Expression
By searching databases for SLC25 family members, Haitina et al. (2006) identified 2 splice variants of SLC25A42. The deduced protein contains 418 amino acids. Quantitative real-time PCR detected variable expression in all rat tissues examined, with highest expression in adipose, followed by hypothalamus and brain coronal sections containing corpus callosum, fornix, thalamus, hypothalamus, optic chiasm, pons, midbrain, and cerebellum.

▼ Gene Structure
Haitina et al. (2006) determined that the SLC25A42 gene contains 7 exons.

▼ Mapping
By genomic sequence analysis, Haitina et al. (2006) mapped the SLC25A42 gene to chromosome 19. They mapped the mouse gene to chromosome 8.

▼ Molecular Genetics
In a 16-year-old boy, born of consanguineous Saudi parents, with recurrent metabolic crises with variable encephalomyopathic features and neurologic regression (MECREN; 618416), Shamseldin et al. (2016) identified a homozygous missense mutation in the SLC25A42 gene (N291D; 610823.0001). The mutation, which was found by exome analysis, segregated with the disorder in the family and was not found in the ExAC database or in 700 in-house control exomes. Molecular modeling suggested that the N291 residue faces the interior of the substrate-binding groove. The mutation was unable to rescue the motor-deficit phenotype in zebrafish with morpholino knockdown of the slc25a42 gene, suggesting that the mutation resulted in a loss of function.

Almannai et al. (2018) identified a homozygous N291D mutation in the SLC25A42 gene in 12 patients from 8 unrelated consanguineous families with MECREN. The phenotype was highly variable, even within families, and the authors suggested that exogenous factors and stressors can modulate disease severity. Functional studies of the variant and studies of patient cells were not performed.

Iuso et al. (2019) identified a homozygous N291D mutation in a Saudi boy with MECREN. An unrelated German boy with the disorder was homozygous for a splice site mutation (610823.0002). Analysis of cells from the German patient did not show the canonical SLC25A42 transcript, but instead showed 3 abnormal transcripts. Total cellular CoA was reduced by about 20% in patient fibroblasts compared to controls. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were found in heterozygous state in all unaffected parents, confirming segregation.

▼ Animal Model
Shamseldin et al. (2016) found that morpholino knockdown of the slc25a42 gene in zebrafish resulted in defects in early motor development, muscle weakness, and bent tails. Mutant animals also had severe muscle disorganization with mitochondrial abnormalities, including fragmented inner mitochondrial membrane and absence of the dense membranous network observed in controls.

▼ ALLELIC VARIANTS ( 2 Selected Examples):

.0001 METABOLIC CRISES, RECURRENT, WITH VARIABLE ENCEPHALOMYOPATHIC FEATURES AND NEUROLOGIC REGRESSION
SLC25A42, ASN291ASP
In a 16-year-old boy, born of consanguineous Saudi parents, with recurrent metabolic crises with variable encephalomyopathic features and neurologic regression (MECREN; 618416), (618416), Shamseldin et al. (2016) identified a homozygous c.871A-G transition (c.871A-G, NM_178526) in the SLC25A42 gene, resulting in an asn291-to-asp (N291D) substitution at a highly conserved residue. The mutation, which was found by exome analysis, segregated with the disorder in the family and was not found in the ExAC database or in 700 in-house control exomes. Molecular modeling suggested that the N291 residue faces the interior of the substrate-binding groove. The mutation was unable to rescue the motor-deficit phenotype in zebrafish with morpholino knockdown of the slc25a42 gene, suggesting that the mutation resulted in a loss of function.

Almannai et al. (2018) identified a homozygous N291D mutation in the SLC25A42 gene in 12 patients from 8 unrelated consanguineous Middle Eastern families with MECREN. The phenotype was highly variable, even within families, and the authors suggested that exogenous factors and stressors can modulate disease severity. Functional studies of the variant and studies of patient cells were not performed. The authors referred to N291D as a founder allele in this population.

Iuso et al. (2019) identified a homozygous N291D mutation in a 6-year-old boy, born of consanguineous Saudi parents, with MECREN. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was found in heterozygous state in each unaffected parent, confirming segregation. Functional studies of the variant and studies of patient cells were not performed.

.0002 METABOLIC CRISES, RECURRENT, WITH VARIABLE ENCEPHALOMYOPATHIC FEATURES AND NEUROLOGIC REGRESSION
SLC25A42, IVS5DS, T-A, +2
In a 9-year-old German boy, born of unrelated parents, with recurrent metabolic crises with variable encephalomyopathic features and neurologic regression (MECREN; 618416), Iuso et al. (2019) identified a homozygous T-to-A transversion in intron 5 of the SLC25A42 gene (c.380+2T-A, NM_178526.4), resulting in a splice site alteration. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was found in heterozygous state in the unaffected parents, confirming segregation. The variant was found once in heterozygous state in the gnomAD database. Analysis of patient cells did not show the canonical SLC25A42 transcript, but instead showed 3 abnormal transcripts. Total cellular CoA was reduced by about 20% in patient fibroblasts compared to controls.

Tags: 19p13.11