Gene/Protein Disease Symptom Drug Enzyme Compound
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 11,717 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Polymerase gamma 1 (POLG) mutations are a frequent cause of both autosomal dominant and recessive complex neurological phenotypes. In contrast, only a single pathogenic mutation in one patient was reported in POLG2 so far. Here we describe a 62-year-old woman, carrying a novel heterozygous sequence variant in the POLG2 gene. She developed bilateral ptosis at 30 years of age, followed by exercise intolerance, muscle weakness and mild CK increase in her late forties. Muscle histology and respiratory chain activities were normal. Southern blot and long range PCR detected multiple mtDNA deletions, but no depletion in muscle DNA. Sequencing of POLG, PEO1, ANT1, OPA1 and RRM2B showed normal results. A novel heteroallelic 24 bp insertion (c.1207_1208ins24) was detected in POLG2. This 24 bp insertion into exon 7 causes missplicing and loss of exon 7 in myoblast cDNA. We did not detect POLG2 mutations in 62 patients with multiple mtDNA deletions in muscle DNA, suggesting that POLG2 mutations may represent a rare cause of autosomal dominant PEO.
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PMID:Late-onset ptosis and myopathy in a patient with a heterozygous insertion in POLG2. 2040 37

The objective is to describe the clinical phenotype and genetic basis of a family with autosomal dominant progressive external ophthalmoplegia and parkinsonism with a Twinkle mutation. The proband, an 82 years old female, reported since childhood bilateral eyelid ptosis, ophthalmoplegia, sensorineural hypoacusis, mild depression since she was 45, with a positive familiar anamnesis of eyelid ptosis (father, two sisters and a son). She developed mild bilateral parkinsonism with a moderate clinical response to levodopa. The (123)I-FP-CIT SCAN evidenced a marked bilateral putaminal reduction and moderate caudate uptake reduction. Her 79 years old sister reported eyelid ptosis since she was 45 with ophthalmoplegia and developed a mild bilateral rest and postural tremor with moderate right arm plastic hypertonia when she was 76. The parkinsonism was confirmed with (123)I-FP-CIT SCAN. One of the two sons presented eyelid ptosis since he was 30 years old, with peripheral neuropathy with biopsy evidence of myopathy. We identified a G1750A mutation in the c10orf2 gene in the three patients. Mitochondrial dysfunction has been implicated in the pathogenesis of sporadic, idiopathic Parkinson disease (PD). In some cases, mitochondrial DNA primary genetic abnormalities or more commonly secondary rearrangements due to polymerase gamma (POLG) gene mutation can directly cause parkinsonism. Parkinsonism has been reported as a rare symptom associated to Twinkle (c10orf2). Parkinsonism has to be investigated in patients with PEO with analysis of Twinkle mutation.
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PMID:Twinkle mutation in an Italian family with external progressive ophthalmoplegia and parkinsonism: a case report and an update on the state of art. 2407 37

Autosomal dominant progressive external ophthalmoplegia (adPEO) is a late-onset, Mendelian mitochondrial disorder characterised by paresis of the extraocular muscles, ptosis, and skeletal-muscle restricted multiple mitochondrial DNA (mtDNA) deletions. Although dominantly inherited, pathogenic variants in POLG, TWNK and RRM2B are among the most common genetic defects of adPEO, identification of novel candidate genes and the underlying pathomechanisms remains challenging. We report the clinical, genetic and molecular investigations of a patient who presented in the seventh decade of life with PEO. Oxidative histochemistry revealed cytochrome c oxidase-deficient fibres and occasional ragged red fibres showing subsarcolemmal mitochondrial accumulation in skeletal muscle, while molecular studies identified the presence of multiple mtDNA deletions. Negative candidate screening of known nuclear genes associated with PEO prompted diagnostic exome sequencing, leading to the prioritisation of a novel heterozygous c.547G>C variant in GMPR (NM_006877.3) encoding guanosine monophosphate reductase, a cytosolic enzyme required for maintaining the cellular balance of adenine and guanine nucleotides. We show that the novel c.547G>C variant causes aberrant splicing, decreased GMPR protein levels in patient skeletal muscle, proliferating and quiescent cells, and is associated with subtle changes in nucleotide homeostasis protein levels and evidence of disturbed mtDNA maintenance in skeletal muscle. Despite confirmation of GMPR deficiency, demonstrating marked defects of mtDNA replication or nucleotide homeostasis in patient cells proved challenging. Our study proposes that GMPR is the 19th locus for PEO and highlights the complexities of uncovering disease mechanisms in late-onset PEO phenotypes.
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PMID:Identification of a novel heterozygous guanosine monophosphate reductase (GMPR) variant in a patient with a late-onset disorder of mitochondrial DNA maintenance. 3160 Aug 44