PUBLICATION
Mutations in ATP13A2 (PARK9) are associated with an amyotrophic lateral sclerosis-like phenotype, implicating this locus in further phenotypic expansion
- Authors
- Spataro, R., Kousi, M., Farhan, S.M.K., Willer, J.R., Ross, J.P., Dion, P.A., Rouleau, G.A., Daly, M.J., Neale, B.M., La Bella, V., Katsanis, N.
- ID
- ZDB-PUB-190418-14
- Date
- 2019
- Source
- Human genomics 13: 19 (Journal)
- Registered Authors
- Katsanis, Nicholas
- Keywords
- none
- MeSH Terms
-
- Adult
- Amyotrophic Lateral Sclerosis/genetics*
- Amyotrophic Lateral Sclerosis/pathology
- Animals
- Disease Models, Animal
- Exome Sequencing
- Female
- Genetic Predisposition to Disease*
- Humans
- Male
- Middle Aged
- Motor Neurons/pathology
- Mutation/genetics
- Neuronal Ceroid-Lipofuscinoses/genetics
- Neuronal Ceroid-Lipofuscinoses/pathology
- Parkinsonian Disorders/genetics
- Parkinsonian Disorders/pathology
- Pedigree
- Phenotype
- Proton-Translocating ATPases/genetics*
- Zebrafish
- PubMed
- 30992063 Full text @ Hum. Genomics
Citation
Spataro, R., Kousi, M., Farhan, S.M.K., Willer, J.R., Ross, J.P., Dion, P.A., Rouleau, G.A., Daly, M.J., Neale, B.M., La Bella, V., Katsanis, N. (2019) Mutations in ATP13A2 (PARK9) are associated with an amyotrophic lateral sclerosis-like phenotype, implicating this locus in further phenotypic expansion. Human genomics. 13:19.
Abstract
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 genes have been implicated as causative in ALS with C9orf72, SOD1, FUS, and TARDBP accounting for the majority of genetically positive cases.
Results We identified two patients of Italian and French ancestry with a clinical diagnosis of juvenile-onset ALS who were mutation-negative in any of the known ALS causative genes. Starting with the index case, a consanguineous family of Italian origin, we performed whole-exome sequencing and identified candidate pathogenic mutations in 35 genes, 27 of which were homozygous. We next parsed all candidates against a cohort of 3641 ALS cases; only ATP13A2 was found to harbor recessive changes, in a patient with juvenile-onset ALS, similar to the index case. In vivo complementation of ATP13A2 using a zebrafish surrogate model that focused on the assessment of motor neuron morphology and cerebellar integrity confirmed the role of this gene in central and peripheral nervous system maintenance and corroborated the damaging direction of effect 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 previously comprised Kufor-Rakeb syndrome, spastic paraplegia 78, and neuronal ceroid lipofuscinosis type 12 (CLN12), to also include juvenile-onset ALS, as supported by both genetic and functional data. Our findings highlight the importance of establishing a complete genetic profile towards obtaining an accurate clinical diagnosis.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping