SURF1-associated leigh syndrome: A case series and novel mutations

Abstract

Leigh syndrome (LS) is a mitochondrial disease that typically presents in infancy with subacute neurodegenerative encephalopathy. It is genetically heterogeneous, but mutations in the complex IV assembly genes, particularly SURF1, are an important cause. In this study, SURF1 gene was sequenced in 590 patients with clinical suspicion of LS, complex IV deficiency, or clinical features of mitochondrial disorders. We identified 21 patients with clinical features of LS who are either homozygous or compound heterozygous for SURF1 mutations. Twenty-two different mutations were identified, including 13 novel mutations. Of the 42 mutant alleles, 36 (86%) are null mutations (frameshift, splicing, or nonsense) and 6 (14%) are missense. We have also reviewed the previously reported SURF1 mutations and observed a clustering of mutation in exon 8 of SURF1, suggesting a vital function for this region. Although mutations in SURF1 have been mainly associated with typical LS, five of the patients in this report had an atypical course of LS. There is no definite genotype-phenotype correlation; however, frameshift mutations resulting in protein truncation closer to the C-terminus may carry a better prognosis.

Identification of a novel deletion in SURF1 gene: Heterogeneity in Leigh syndrome with COX deficiency

“…2A and C). This alteration was absent in 200 DNA samples of healthy subjects and it was not reported in any public SNP databases or in recent publications (Lee et al, 2012;Wedatilake et al, 2013). The deletion is located in a highly conserved region ( Fig.…”

“…So far, N 78 mutations were found in SURF1, and about 80% probably lead to the production of truncated proteins, mainly due to aberrant splicing, frameshift, deletions or nonsense mutations (Wedatilake et al, 2013). The majority of SURF1 mutations previously associated to LS, are located in exon 8, suggesting that this region has an important impact in the protein function or it is a hot spot for the occurrence of mutations (Lee et al, 2012).…”

“…Patients with SURF1-associated LS have a poor prognosis and usually die in the first decade of life (Lee et al, 2012). According to Aulbert et al in 2014, a total of 15 patients with survival higher than 14 years have been reported and the oldest patient with LS associated to SURF1 mutations was a woman with 22 years old (Lee et al, 2012;Aulbert et al, 2014). This patient had two mutations that were predicted to generate truncated proteins at amino acid positions 248 and 279.…”

“…This patient had two mutations that were predicted to generate truncated proteins at amino acid positions 248 and 279. According to the authors, the milder phenotype could be explained by the fact that those alterations occur near the Cterminus of the protein and it could have some residual function (Lee et al, 2012).…”

Genetic Counseling in Mitochondrial Disease

“…Identifying the AR inheritance in this family history can help to direct the nDNA testing. SURF1 mutations have been identified in a number of individuals with Leigh's or Leigh's-like disease, and/or complex IV deficiency [6]. While AR conditions are evident with the presence of consanguinity and/or affected sibling(s), it remains important to consider this inheritance pattern in many childhood-onset mitochondrial diseases in the absence of a suspicious family history.…”