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Novel homozygous nonsense mutation in the P5'N-1 coding gene as an alternative cause for hereditary anemia with basophilic stippling.

ABSTRACT: Hereditary pyrimidine 5-nucleotidase (P5'N-1) deficiency is a very rare disorder. Here, we describe a new mutation in a Turkish family. Although functional tests have not been performed, our findings confirm that the homozygous mutational state leads to clinical manifest P5'N-1 deficiency, while heterozygosity does not lead to hemolysis or anemia.

SUBMITTER: Kirschner M

PROVIDER: S-EPMC8895901 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Novel homozygous nonsense mutation in the P5'N-1 coding gene as an alternative cause for hereditary anemia with basophilic stippling.

Kirschner Martin M Heinen Inga Rebecca IR Koschmieder Steffen S Manco Licinio L Bento Celeste C Eggermann Thomas T Kurth Ingo I Jost Edgar E Brümmendorf Tim H TH Fuchs Roland R

Clinical case reports 20220304 3

Hereditary pyrimidine 5-nucleotidase (P5'N-1) deficiency is a very rare disorder. Here, we describe a new mutation in a Turkish family. Although functional tests have not been performed, our findings confirm that the homozygous mutational state leads to clinical manifest P5'N-1 deficiency, while heterozygosity does not lead to hemolysis or anemia. ...[more]

PMID: 35280089

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Project description:Distal hereditary motor neuropathy represents a group of motor inherited neuropathies leading to distal weakness. We report a family of two brothers and a sister affected by distal hereditary motor neuropathy in whom a homozygous variant c.3G>T (p.1Met?) was identified in the COQ7 gene. This gene encodes a protein required for coenzyme Q10 biosynthesis, a component of the respiratory chain in mitochondria. Mutations of COQ7 were previously associated with severe multi-organ disorders characterized by early childhood onset and developmental delay. Using patient blood samples and fibroblasts derived from a skin biopsy, we investigated the pathogenicity of the variant of unknown significance c.3G>T (p.1Met?) in the COQ7 gene and the effect of coenzyme Q10 supplementation in vitro. We showed that this variation leads to a severe decrease in COQ7 protein levels in the patient's fibroblasts, resulting in a decrease in coenzyme Q10 production and in the accumulation of 6-demethoxycoenzyme Q10, the COQ7 substrate. Interestingly, such accumulation was also found in the patient's plasma. Normal coenzyme Q10 and 6-demethoxycoenzyme Q10 levels were restored in vitro by using the coenzyme Q10 precursor 2,4-dihydroxybenzoic acid, thus bypassing the COQ7 requirement. Coenzyme Q10 biosynthesis deficiency is known to impair the mitochondrial respiratory chain. Seahorse experiments showed that the patient's cells mainly rely on glycolysis to maintain sufficient ATP production. Consistently, the replacement of glucose by galactose in the culture medium of these cells reduced their proliferation rate. Interestingly, normal proliferation was restored by coenzyme Q10 supplementation of the culture medium, suggesting a therapeutic avenue for these patients. Altogether, we have identified the first example of recessive distal hereditary motor neuropathy caused by a homozygous variation in the COQ7 gene, which should thus be included in the gene panels used to diagnose peripheral inherited neuropathies. Furthermore, 6-demethoxycoenzyme Q10 accumulation in the blood can be used to confirm the pathogenic nature of the mutation. Finally, supplementation with coenzyme Q10 or derivatives should be considered to prevent the progression of COQ7-related peripheral inherited neuropathy in diagnosed patients.

Dataset Information

Novel homozygous nonsense mutation in the P5'N-1 coding gene as an alternative cause for hereditary anemia with basophilic stippling.

Publications

Novel homozygous nonsense mutation in the P5'N-1 coding gene as an alternative cause for hereditary anemia with basophilic stippling.

Similar Datasets

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