Reevaluating the pathogenicity of the variations c.439 G>A and c.2132 C>T in the PLA2G6 gene
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Ó Indian Academy of Sciences (0123456789().,-volV) (0123456789().,-volV)
HYPOTHESIS
Reevaluating the pathogenicity of the variations c.439 G>A and c.2132 C>T in the PLA2G6 gene STEPHANE ALLOUCHE* Laboratoire de Biochimie, Centre Hospitalier et Universitaire, Avenue Co ˆ te de Nacre, 14033 Caen Cedex, France *E-mail: [email protected]. Received 4 August 2020; accepted 18 August 2020 Abstract. The phospholipase A2 group VI (PLA2G6) gene encodes for a Ca2?-independent PLA2, which is localized in the cytosol, in the endoplasmic reticulum and in the mitochondrial membrane, plays a major role in phospholipid remodelling. Mutations within this gene have been reported to cause different phenotypes: infantile-onset neuroaxonal dystrophy associated with brain iron accumulation and adult-onset parkinsonian syndrome. In the present study, we analysed the PLA2G6 gene sequence in an asymptomatic young woman that was referred to our laboratory by a geneticist for an history of infantile neuroaxonal dystrophy in her little maternal cousin in whom the results of the genetical analysis were not available. We found two variants in the PLA2G6 gene (NM_003560.4, c.439 G[A and c.2132 C[T, p.Ala147Thr and p.Pro711Leu) previously reported as pathogenic. These results prompted us to perform a segregation analysis in the parents of this woman and we only found the presence of both variants in the asymptomatic 56-year-old patient’s mother. Our molecular genetic testing clearly indicates that the c.439 G[A and c.2132 C[T variations identified in the PLA2G6 gene are positioned in cis and are not responsible for infantile neuroaxonal dystrophy which is an autosomal recessive disease. Keywords.
PLA2G6 gene; infantile neuroaxonal dystrophy; mitochondria.
The phospholipase A2 superfamily is constituted by enzymes which catalyze the hydrolysis of glycerophospholipids at the sn-2 position to produce free fatty acids and lysophospholipids. Among the different family members, the PLA2G6 is characterized by an enzymatic activity which does not require Ca2? and is located in the cytosol, endoplasmic reticulum and mitochondria (see review of Smani et al. 2016). Mutations in the PLA2G6 gene have been associated with neurodegeneration of brain iron accumulation (NBIA) disorders (Gregory and Hayflick 2013). Four different subtypes, including infantile neuroaxonal dystrophy (INAD), can be differentiated based on the clinical symptoms and the age at the onset (Guo et al. 2018). INAD is an autosomal recessive disorder with an early age of onset and is characterized by a progressive psychomotor deterioration, hypotonia, cerebellar ataxia, extrapyramidal signs and visual abnormality. During the progression of the disease, iron accumulation can be detected by MRI affecting the basal ganglia, especially the globus pallidus and the substantia nigra. In 2008, Gregory and collaborators
reported PLA2G6 mutations in 56 patients clinically diagnosed with INAD (Gregory et al. 2008). Among those mutations, they found compound heterozygous missense (c.439 G[A and c
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