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PDXK mutations cause polyneuropathy responsive to pyridoxal 5'-phosphate supplementation.

ABSTRACT: OBJECTIVE:To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. METHODS:We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient-derived fibroblasts, plasma, and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology, and biochemical quantification. RESULTS:We identified biallelic mutations in PDXK in 5 individuals from 2 unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair-bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP-binding pocket. Low PDXK ATP binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5'-phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization. INTERPRETATION:We show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225-240.

SUBMITTER: Chelban V

PROVIDER: S-EPMC6772106 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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PDXK mutations cause polyneuropathy responsive to pyridoxal 5'-phosphate supplementation.

Chelban Viorica V Wilson Matthew P MP Warman Chardon Jodi J Vandrovcova Jana J Zanetti M Natalia MN Zamba-Papanicolaou Eleni E Efthymiou Stephanie S Pope Simon S Conte Maria R MR Abis Giancarlo G Liu Yo-Tsen YT Tribollet Eloise E Haridy Nourelhoda A NA Botía Juan A JA Ryten Mina M Nicolaou Paschalis P Minaidou Anna A Christodoulou Kyproula K Kernohan Kristin D KD Eaton Alison A Osmond Matthew M Ito Yoko Y Bourque Pierre P Jepson James E C JEC Bello Oscar O Bremner Fion F Cordivari Carla C Reilly Mary M MM Foiani Martha M Heslegrave Amanda A Zetterberg Henrik H Heales Simon J R SJR Wood Nicholas W NW Rothman James E JE Boycott Kym M KM Mills Philippa B PB Clayton Peter T PT Houlden Henry H

Annals of neurology 20190701 2

<h4>Objective</h4>To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy.<h4>Methods</h4>We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding. Pathogenicity was f ...[more]

PMID: 31187503

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Project description:Parkinson's disease is a neurodegenerative disorder with a multifactorial aetiology. Nevertheless, the genetic predisposition in many families with multi-incidence disease remains unknown. This study aimed to identify novel genes that cause familial Parkinson's disease. Whole exome sequencing was performed in three affected members of the index family with a late-onset autosomal-dominant parkinsonism and polyneuropathy. We identified a novel heterozygous substitution c.941A>C (p.Tyr314Ser) in the mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) gene, which co-segregates with disease within the family. Additional analysis of 699 unrelated Parkinson's disease probands with autosomal-dominant Parkinson's disease and 1934 patients with sporadic Parkinson's disease revealed another two variants in UQCRC1 in the probands with familial Parkinson's disease, c.931A>C (p.Ile311Leu) and an allele with concomitant splicing mutation (c.70-1G>A) and a frameshift insertion (c.73_74insG, p.Ala25Glyfs*27). All substitutions were absent in 1077 controls and the Taiwan Biobank exome database from healthy participants (n = 1517 exomes). We then assayed the pathogenicity of the identified rare variants using CRISPR/Cas9-based knock-in human dopaminergic SH-SY5Y cell lines, Drosophila and mouse models. Mutant UQCRC1 expression leads to neurite degeneration and mitochondrial respiratory chain dysfunction in SH-SY5Y cells. UQCRC1 p.Tyr314Ser knock-in Drosophila and mouse models exhibit age-dependent locomotor defects, dopaminergic neuronal loss, peripheral neuropathy, impaired respiratory chain complex III activity and aberrant mitochondrial ultrastructures in nigral neurons. Furthermore, intraperitoneal injection of levodopa could significantly improve the motor dysfunction in UQCRC1 p.Tyr314Ser mutant knock-in mice. Taken together, our in vitro and in vivo studies support the functional pathogenicity of rare UQCRC1 variants in familial parkinsonism. Our findings expand an additional link of mitochondrial complex III dysfunction in Parkinson's disease.

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PDXK mutations cause polyneuropathy responsive to pyridoxal 5'-phosphate supplementation.

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PDXK mutations cause polyneuropathy responsive to pyridoxal 5'-phosphate supplementation.

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