Mutations in PNPLA6 Cause a Range of Neurodegenerative Phenotypes. M. A. Gonzalez1, M. Synofzik2, M. Coutelier3, C. Marques Lourenço4, T. Haack5, H. Prokisch5, R. Schule2, W. Marques Junior4, L. Schols2, G. Stevanin3, S. Zuchner1 1) Human Genetics and Genomics, Unviersity of Miami Miller School of Medicine, Miami, FL; 2) Hertie Institute for Clinical Brain Research and Center for Neurology, Department of Neurodegenerative Disease, University of Tübingen, Germany; 3) Université Pierre-et-Marie-Curie, Universite Paris VI, Centre de Recherche de lInstitut du Cerveau et de la Moelle epiniere, EPHE, and Centre national de la recherche scientifique, Unité mixte de recherche 7225, Groupe Hospitalier Pitie-Salpêtriere; 4) Department of Neuroscience and Behaviour Sciences, School of Medicine of Ribeirão Preto, University of Sao Polo, Brazil; 5) Institute of Human Genetics, Technische Universität München, Germany.

   The large amount of exome sequencing data across related and unrelated diseases has allowed supporting known, and defining new, spectra of phenotypes. Ataxia is a common symptom of a number of neurodegenerative diseases, including spinal ataxias, some forms of complicated hereditary spastic paraplegias (cHSP), and rare syndromes. With ataxia as a defining symptom we have searched across 936 exomes for common recessive genes using the GEnomes Management Application ( We have identified PNPLA6 variants as an important and repeated cause in multiple (now deemed related) phenotypes. Boucher-Neuhäuser syndrome (BNS) is a rare autosomal recessive disorder characterized by spinocerebellar ataxia, chorioretinal dystrophy, and a failure of the pituitary to stimulate gonadal development during puberty. Three BNS families had causative PNPLA6 mutations. A Holmes syndrome family carried compound heterozygous mutations in PNPLA6. Mutations in PNPLA6 were previously described in two cHSP families. We identified PNPLA6 mutations in an additional cHSP family and also in a spastic ataxia family. In total, we report 6 families with homozygous or compound heterozygous mutations in PNPLA6. The majority of mutations clustered on the C-terminal catalytic domain, which has been shown to have esterase activity and phospholipase activity for lysophosphatidylcholine (LPC) and phosphatidylcholine (PC). LPC is the result of partial hydryolysis and removal of one of the fatty acids groups of PC. Alteration of phospholipid metabolism has been shown to impact mitochondrial function, which is hypothesized to be critical for the functions of the long axons of the corticospinal tracts. This adds to recently identified genes (DDHD1, DDHD2, CYP2U1 and others), which have highlighted the importance of phospholipase enzyme activity in neurodegeneration. In conclusion, our findings demonstrate that PNPLA6 mutations cause a range of neurodegenerative diseases creating a hitherto not recognized biological connection between several distinct clinical phenotypes.

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