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SUCCINATE DEHYDROGENASE COMPLEX ASSEMBLY FACTOR 1; SDHAF1

SUCCINATE DEHYDROGENASE COMPLEX ASSEMBLY FACTOR 1; SDHAF1

HGNC Approved Gene Symbol: SDHAF1Cytogenetic location: 19q13.12 Genomic coordinates (GRCh38): 19:35,995,187-35,996,311 (from NCBI)▼ DescriptionThe succinate ...

HGNC Approved Gene Symbol: SDHAF1

Cytogenetic location: 19q13.12 Genomic coordinates (GRCh38): 19:35,995,187-35,996,311 (from NCBI)

▼ Description

The succinate dehydrogenase (SDH) complex, or complex II of the mitochondrial respiratory chain, is composed of 4 individual subunits (see SDHA, 600857). SDHAF1 is essential for SDH assembly but does not physically associate with the complex in vivo (Ghezzi et al., 2009).

▼ Cloning and Expression

Using PCR of genomic DNA, Ghezzi et al. (2009) cloned full-length SDHAF1. The deduced 115-amino acid protein has an N-terminal mitochondrial targeting sequence and an LYR motif characteristic of proteins involved in Fe-S metabolism. Northern blot analysis detected SDHAF1 in all tissues examined. Epitope-tagged SDHAF1 localized to mitochondria in transfected COS-7 and HeLa cells. Western blot analysis and subcellular fractionation suggested that SDHAF1 resides in the mitochondrial matrix and that the mitochondrial targeting signal is not removed following import into mitochondria.

▼ Gene Structure

Ghezzi et al. (2009) determined that the SDHAF1 gene contains a single exon.

▼ Mapping

By linkage and genomic sequence analysis, Ghezzi et al. (2009) mapped the SDHAF1 gene to chromosome 19q12-q13.2.

▼ Molecular Genetics

In affected members of an Italian and a Turkish family with mitochondrial complex II deficiency type 2 (MC2DN2; 619166), Ghezzi et al. (2009) identified different homozygous mutations in the SDHAF1 gene (G57R, 612848.0001 and R55P, 612848.0002, respectively).

In 5 patients with MC2DN2, Ohlenbusch et al. (2012) identified homozygous mutations in the SDHAF1 gene: the G57R mutation in 2 additional members of the large Turkish family reported by Ghezzi et al. (2009); Q8X (612848.0003) in a Norwegian boy previously reported by Brockmann et al. (2002); and G57E (612848.0004) in Palestinian sisters.

▼ ALLELIC VARIANTS ( 4 Selected Examples):

.0001 MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 2
SDHAF1, GLY57ARG

In affected members of an Italian family with mitochondrial complex II deficiency nuclear type 2 (MC2DN2; 619166), Ghezzi et al. (2009) identified a homozygous c.169G-C transversion in the SDHAF1 gene, resulting in a gly57-to-arg (G57R) substitution. The mutation was not identified in 660 European or 150 Turkish controls. Biochemical studies in patient cells showed 20 to 30% residual activity of SDH. Expression of wildtype SDHAF1 in G57R-mutant fibroblast cell lines resulted in recovery of SDH. The family was previously reported by Bugiani et al. (2006).

.0002 MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 2
SDHAF1, ARG55PRO

In affected members of a consanguineous Turkish family with mitochondrial complex II deficiency nuclear type 2 (MC2DN2; 619166), Ghezzi et al. (2009) identified a homozygous c.164G-C transversion in the SDHAF1 gene, resulting in an arg55-to-pro (R55P) substitution. The mutation was not identified in 660 European or 150 Turkish controls. The family was previously reported by Brockmann et al. (2002).

Ohlenbusch et al. (2012) identified 2 German sisters of Turkish origin (patients 1 and 2, family A) with MC2DN2 and a homozygous R55P mutation who were part of the large pedigree reported by Ghezzi et al. (2009). The parents were consanguineous and heterozygous for the mutation. The sibs, who died at age 18 months and 11 years, had leukoencephalopathy, an elevated succinate peak on brain MR spectroscopy and decreased respiratory complex II activity in fibroblasts. The sib who died at age 18 months also had decreased respiratory complex II activity in muscle.

.0003 MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 2
SDHAF1, GLN8TER

In a 16-year-old Norwegian boy (patient 3, family B) with mitochondrial complex II deficiency nuclear type 2 (MC2DN2; 619166), Ohlenbusch et al. (2012) identified a homozygous c.22C-T transition (GenBank NC_000019.9) in the SDHAF1 gene, resulting in a gln8-to-ter (G8X) substitution. The mutation segregated with the disorder in the family. The patient was previously reported by Brockmann et al. (2002).

.0004 MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 2
SDHAF1, GLY57GLU

In 2 sisters (patients 4 and 5, family C), born to consanguineous Palestinian parents, with mitochondrial complex II deficiency nuclear type 2 (MC2DN2; 619166), Ohlenbusch et al. (2012) identified a homozygous c.170G-A transition (GenBank NC_000019.9) in the SDHAF1 gene, resulting in a gly57-to-glu (G57E) substitution at a highly conserved residue.

Tags: 19q13.12