SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease

Abstract

Objective: To investigate whether mutations in the SURF1 gene are a cause of Charcot-MarieTooth (CMT) disease. Methods:We describe 2 patients from a consanguineous family with demyelinating autosomal recessive CMT disease (CMT4) associated with the homozygous splice site mutation c.107-2A.G in the SURF1 gene, encoding an assembly factor of the mitochondrial respiratory chain complex IV. This observation led us to hypothesize that mutations in SURF1 might be an unrecognized cause of CMT4, and we investigated SURF1 in a total of 40 unrelated patients with CMT4 after exclusion of mutations in known CMT4 genes. The functional impact of c.107-2A.G on splicing, amount of SURF1 protein, and on complex IV activity and assembly was analyzed.Results: Another patient with CMT4 was found to harbor 2 additional SURF1 mutations. All 3 patients with SURF1-associated CMT4 presented with severe childhood-onset neuropathy, motor nerve conduction velocities ,25 m/s, and lactic acidosis. Two patients had brain MRI abnormalities, including putaminal and periaqueductal lesions, and developed cerebellar ataxia years after polyneuropathy. The c.107-2A.G mutation produced no normally spliced transcript, leading to SURF1 absence. However, complex IV remained partially functional in muscle and fibroblasts. Conclusions:We found SURF1 mutations in 5% of families (2/41) presenting with CMT4. SURF1 should be systematically screened in patients with childhood-onset severe demyelinating neuropathy and additional features such as lactic acidosis, brain MRI abnormalities, and cerebellar ataxia developing years after polyneuropathy. Peripheral neuropathies are a well-known complication of mitochondrial DNA and nuclearencoded mitochondrial gene mutations. For instance, patients with mutations in the nuclearencoded mitochondrial genes MFN2 and GDAP1, which encode outer mitochondrial membrane proteins, usually present with axonal and demyelinating forms of Charcot-Marie-Tooth (CMT) disease, respectively.1 Moreover, patients with mutations in the mitochondrial DNA gene MTATP6, which encodes the ATP6 subunit of the mitochondrial respiratory chain (MRC) complex V, may present with axonal CMT (CMT2). 2The determination of the genetic cause is a major challenge in rare neuromuscular diseases such as autosomal recessive demyelinating CMT (CMT4). We investigated a consanguineous family in which 2 patients with CMT4 harbored a homozygous splice site mutation in SURF1, encoding an assembly factor of the MRC complex IV (cytochrome c oxidase [COX]). Despite this defect, we detected some residual assembly and function of COX in fibroblasts and muscle of both patients. We then screened for SURF1 mutations in a cohort of 40 unrelated patients

Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy

“…Compound heterozygous truncating mutations in SURF1 were identified in a proband with demyelinating CMT. Loss of function mutations in SURF1 were recently described in patients with autosomal recessive severe demyelinating neuropathy of childhood onset [Echaniz-Laguna, 2013], consistent with this patient’s clinical and molecular findings.…”

Alternative Splicing in the HumanPMP22Gene: Implications in CMT1A Neuropathy

“…Interestingly, mutations of proteins involved in alternative splicing, such as the RNA‐binding protein quaking I (QKI; MIM #609590), result in severe central and peripheral dys/demyelination [Mandler et al., ]. Indeed, mutations and genetic rearrangements occurring in CMT neuropathies disrupt alternative splicing and several myelin genes are alternatively spliced, including myelin basic protein (MBP), proteolipid protein (PLP), myelin‐associated glycoprotein MAG [Regis et al., ; Lassuthova et al., ; Padhi and Pelletier, ; Park et al., ; Echaniz‐Laguna et al., ; Zearfoss et al., ; Tamiya et al., ]. PMP22 has three known variants arising from three distinct primary transcripts.…”

Peripheral neuropathies in mitochondrial disorders

“…In these patients, nerve conduction velocities are decreased and nerve biopsy is suggestive of a myelinopathy, with disproportionately thin myelinated fibers and loss of large myelinated fibers [20]. In some patients, the CNS dysfunction is very limited, appears later than the PNP [21], and lifespan is much longer, two of the three patients reported to date being older than 40 years of age. In one patient, nerve biopsy showed features of chronic demyelinating neuropathy, with moderate axonal loss, presence of onion bulbs, and hypomyelinated fibers [21].…”

“…In some patients, the CNS dysfunction is very limited, appears later than the PNP [21], and lifespan is much longer, two of the three patients reported to date being older than 40 years of age. In one patient, nerve biopsy showed features of chronic demyelinating neuropathy, with moderate axonal loss, presence of onion bulbs, and hypomyelinated fibers [21].…”