Mutations in ATP13A2 (PARK9) are associated with an amyotrophic lateral sclerosis-like phenotype, implicating this locus in further phenotypic expansion

Vincenzo La Bella, Jason R. Willer, Rossella Spataro, Maria Kousi, Sali M K Farhan, Jay P. Ross, Patrick A. Dion, Guy A. Rouleau, Mark J. Daly, Benjamin M. Neale, Nicholas Katsanis

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13 Citazioni (Scopus)


Background: Amyotrophic lateral sclerosis [1] is a genetically heterogeneous neurodegenerative disorder,characterized by late-onset degeneration of motor neurons leading to progressive limb and bulbar weakness,as well as of the respiratory muscles, which is the primary cause of disease fatality. To date, over 25 geneshave been implicated as causative in ALS with C9orf72, SOD1, FUS, and TARDBP accounting for the majority ofgenetically positive cases.Results: We identified two patients of Italian and French ancestry with a clinical diagnosis of juvenile-onsetALS who were mutation-negative in any of the known ALS causative genes. Starting with the index case, aconsanguineous family of Italian origin, we performed whole-exome sequencing and identified candidatepathogenic mutations in 35 genes, 27 of which were homozygous. We next parsed all candidates against acohort of 3641 ALS cases; only ATP13A2 was found to harbor recessive changes, in a patient with juvenileonsetALS, similar to the index case. In vivo complementation of ATP13A2 using a zebrafish surrogate modelthat focused on the assessment of motor neuron morphology and cerebellar integrity confirmed the role ofthis gene in central and peripheral nervous system maintenance and corroborated the damaging direction ofeffect of the change detected in the index case of this study.Conclusions: We here expand the phenotypic spectrum associated with genetic variants in ATP13A2 that previouslycomprised Kufor-Rakeb syndrome, spastic paraplegia 78, and neuronal ceroid lipofuscinosis type 12 (CLN12), to alsoinclude juvenile-onset ALS, as supported by both genetic and functional data. Our findings highlight the importance ofestablishing a complete genetic profile towards obtaining an accurate clinical diagnosis.
Lingua originaleEnglish
Numero di pagine10
RivistaHuman Genetics
Stato di pubblicazionePublished - 2019

All Science Journal Classification (ASJC) codes

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