ATP8A2-related disorders as recessive cerebellar ataxia
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ATP8A2-related disorders are autosomal recessive conditions that associate encephalopathy with or without hypotonia, psychomotor delay, abnormal movements, chorea, tremor, optic atrophy and cerebellar atrophy (CARMQ4). Through a multi-centric collaboration, we identified six point mutations (one splice site and five missense mutations) involving ATP8A2 in six individuals from five families. Two patients from one family with the homozygous p.Gly585Val mutation had a milder presentation without encephalopathy. Expression and functional studies of the missense mutations demonstrated that protein levels of four of the five missense variants were very low and lacked phosphatidylserine-activated ATPase activity. One variant p.Ile215Leu, however, expressed at normal levels and displayed phospholipid-activated ATPase activity similar to the non-mutated protein. We therefore expand for the first time the phenotype related to ATP8A2 mutations to less severe forms characterized by cerebellar ataxia without encephalopathy and suggest that ATP8A2 should be analyzed for all cases of syndromic or non-syndromic recessive or sporadic ataxia.
KeywordsAtaxia ATP8A2 CAMRQ P4-ATPase Psychomotor delay
The authors thank the families and patients described herein for their participation in this study. The corresponding author had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. This study was supported by funds from the Agence Nationale pour la Recherche (ANR)/E-rare Joint Trans-national Call (JTC) 2011 ‘Euro-SCAR’ (2011-RARE-004–01 to M.K.) and the Canadian Institutes of Health Research grant (PJT 148649 to RSM).
CG and MK: conception and design of the study; AH, AC, CG, EAA, HT, IO, KB, LL, MB, MI, MK, NEE, PC, RSM, RT: contributed to acquisition, analysis, and interpretation of data; CG, MB, MK and RSM: contributed to drafting the manuscript or figures; AC, CG, EAA, HT, IO, KB, LL, MB, MC, MI, MK, NEE, PC, RSM, RT: contributed to critical revision of the manuscript, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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Conflicts of interest
The authors declare that they have no conflicts of interest.
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