POLG exon 22 skipping induced by different mechanisms in two unrelated cases of Alpers syndrome

Camaret, Bénédicte Mousson de; Chassagne, Maïté; Mayençon, Martine; Padet, Sylvie; Crehalet, Hervé; Clerc-Renaud, Pascale; Rouvet, Isabelle; Zabot, M. T.; Rivier, François; Sarda, Pierre; Portes, Vincent Des; Bozon, Dominique

doi:10.1016/j.mito.2010.07.011

Cited by 5 publications

(8 citation statements)

References 32 publications

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“…The RC activity of liver (n = 8) was deficient when RC activity in muscle was normal . Conversely, both the liver and muscle from five patients showed RC deficiency . As with fibroblasts, a single brain biopsy was reported to show isolated complex III deficiency …”

Section: Resultsmentioning

confidence: 99%

“…The RC activity was highly variable among different tissues. Normal RC activity and a number of RC defects (isolated and multicomplex deficiencies) were detected. Complex V defects were rarely reported in muscle and liver samples (Table ).…”

Section: Resultsmentioning

confidence: 99%

“…The RC activity was highly variable among different tissues. Normal RC activity 9,21,22,28,32,37,39,40,[44][45][46]51,52,[60][61][62][63][64] and a number of RC defects (isolated and multicomplex deficiencies) 9,13,20,21,30,32,37,38,40,46,[50][51][52]56,57,[61][62][63][64][65][66] were detected. Complex V defects were rarely reported in muscle and liver samples 20,46,51,57 (Table 4).…”

Section: Mitochondrial Respiratory Chain (Rc)mentioning

confidence: 99%

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Epilepsy due to mutations in the mitochondrial polymerase gamma (POLG) gene: A clinical and molecular genetic review

Anagnostou

Taylor

et al. 2016

Epilepsia

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We performed a systematic review of the clinical, molecular, and biochemical features of polymerase gamma (POLG)-related epilepsy and current evidence on seizure management. Patients were identified from a combined electronic search of articles using Ovid Medline and Scopus databases, published from January 2000 to January 2015. Only patients with a confirmed genetic diagnosis of POLG mutations were considered. Seventy-two articles were included for analysis. We identified 128 pathogenic variants in 372 patients who had POLG-related epilepsy. Among these, 84% of the cases harbored at least one of these pathogenic variants: p.Ala467Thr, p.Trp748Ser, and p.Gly848Ser. A bimodal distribution of disease onset was present in early childhood (<5 years) and adolescence; female patients had a later presentation than male patients (median age 4.00 vs. 1.83 years, p-value = 0.041). Focal-onset seizure including convulsive, myoclonus, and occipital seizures was common at the outset and was refractory to pharmacotherapy. We confirmed that homozygous pathogenic variants located in the linker region of POLG were associated with later age of onset and longer survival compared to compound heterozygous variants. In addition, biochemical and molecular heterogeneities in different tissues were frequently observed. POLG-related epilepsy is clinically heterogeneous, and the prognosis is, in part, influenced by the location of the variants in the gene and the presence of hepatic involvement. Normal muscle and fibroblast studies do no exclude the diagnosis of POLG-related mitochondrial disease and direct sequencing of the POLG gene should be the gold standard when investigating suspected cases.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Mitochondrial Respiratory Chain (Rc)mentioning

confidence: 99%

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Epilepsy due to mutations in the mitochondrial polymerase gamma (POLG) gene: A clinical and molecular genetic review

Anagnostou

Taylor

et al. 2016

Epilepsia

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“…RNA samples were free of any contaminating DNA by treatment with the DNA- free Kit (Ambion Inc, Austin, TX, USA). Reverse transcription of 0.3 μg and 1 μg total RNA from muscle and fibroblasts, respectively, was performed as previously described 8. Amplification and sequencing of ANT1 , ANT3 and POLG cDNAs from muscle and cultured fibroblasts were performed with specific primers (not shown).…”

Section: Methodsmentioning

confidence: 99%

Complete loss of expression of theANT1gene causing cardiomyopathy and myopathy

Echaniz‐Laguna

Chassagne²,

Ceresuela³

et al. 2011

J Med Genet

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“…RT of 0.8-1 mg total RNA was performed as described. 4 Amplification of SURF1 complementary DNA (cDNA) was performed with several specific primer pairs. Amplification products were cloned into the pCR2.1-TOPO vector using the TOPO TA Cloning Kit (Invitrogen, Carlsbad, CA).…”

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confidence: 99%

SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease

et al. 2013

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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

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POLG exon 22 skipping induced by different mechanisms in two unrelated cases of Alpers syndrome

Cited by 5 publications

References 32 publications

Epilepsy due to mutations in the mitochondrial polymerase gamma (POLG) gene: A clinical and molecular genetic review

Epilepsy due to mutations in the mitochondrial polymerase gamma (POLG) gene: A clinical and molecular genetic review

Complete loss of expression of theANT1gene causing cardiomyopathy and myopathy

SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease

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