In an Asian girl, born of consanguineous parents, with mitochondrial complex II deficiency nuclear type 4 (MC2DN4; 619224), Alston et al. (2012) identified a homozygous c.143A-T transversion (c.143A-T, NM_003000.2) in exon 2 of the SDHB gene, resulting in an asp48-to-val (D48V) substitution. Her unaffected parents were heterozygous for the mutation. The D48 residue is not conserved between human and yeast, but D48 is conservatively substituted by N42 in the yeast Sdh2 protein (yeast ortholog). Construction of an Sdh2 N42D allele rescued the oxidation growth defect of yeast with a deletion of the Sdh2 gene; the N42D variant showed normal SDH activity. Introduction of an N42V substitution did not impair growth of yeast or oxygen consumption, but did cause decreased SDH activity (about 50% of control). Patient fibroblasts showed decreased amounts of fully assembled complex II and almost complete absence of the SDHB subunit. Complex II activity was also decreased in patient muscle samples.
In a Pakistani girl, born to consanguineous parents, with MC2DN4, Ardissone et al. (2015) identified homozygosity for the D48V mutation in the SDHB gene. The mutation, which was identified by sequencing of a panel of 7 genes associated with complex II deficiency, was confirmed by Sanger sequencing. The parents were confirmed to be carriers, and a clinically unaffected older sib was also homozygous for the mutation. The D48V mutation was observed in ExAC at a low frequency of 0.036% in only South Asian subjects, with no homozygotes reported. SDHB protein expression was reduced in patient fibroblasts and lymphocytes as well as in lymphocytes from the clinically unaffected sib who also homozygous for the mutation.
In a Turkish boy (patient LD_0756.0A) with MC2DN4, who was born of consanguineous parents, Vanderver et al. (2016) identified homozygosity for the D48V mutation in the SDHB gene. The mutation was identified by whole-exome sequencing.
In 5 patients with MC2DN4, Helman et al. (2016) identified the D48V mutation in the SDHB gene. It was present in homozygous state in 4 patients (patients 10, 11, 16, and 19) and in compound heterozygous state in 1 (patient 15).
In a male infant, born on nonconsanguineous parents, with MC2DN4, Gronborg et al. (2017) identified compound heterozygous mutations in the SDHB gene: D48V and a c.689G-A transition resulting in an arg230-to-his (R230H; 185470.0023) substitution. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. The parents were confirmed to be mutation carriers. SDHB protein content was reduced in patient fibroblasts, and muscle fibers showed diffuse and severe lack of SDH staining.
