Loss-of-function mutations in theATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78)

Abstract

Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders characterized by progressive spasticity of the lower limbs due to degeneration of the corticospinal motor neurons. In a Bulgarian family with three siblings affected by complicated hereditary spastic paraplegia, we performed whole exome sequencing and homozygosity mapping and identified a homozygous p.Thr512Ile (c.1535C > T) mutation in ATP13A2. Molecular defects in this gene have been causally associated with Kufor-Rakeb syndrome (#606693), an autosomal recessive form of juvenile-onset parkinsonism, and neuronal ceroid lipofuscinosis (#606693), a neurodegenerative disorder characterized by the intracellular accumulation of autofluorescent lipopigments. Further analysis of 795 index cases with hereditary spastic paraplegia and related disorders revealed two additional families carrying truncating biallelic mutations in ATP13A2. ATP13A2 is a lysosomal P5-type transport ATPase, the activity of which critically depends on catalytic autophosphorylation. Our biochemical and immunocytochemical experiments in COS-1 and HeLa cells and patient-derived fibroblasts demonstrated that the hereditary spastic paraplegia-associated mutations, similarly to the ones causing Kufor-Rakeb syndrome and neuronal ceroid lipofuscinosis, cause loss of ATP13A2 function due to transcript or protein instability and abnormal intracellular localization of the mutant proteins, ultimately impairing the lysosomal and mitochondrial function. Moreover, we provide the first biochemical evidence that disease-causing mutations can affect the catalytic autophosphorylation activity of ATP13A2. Our study adds complicated hereditary spastic paraplegia (SPG78) to the clinical continuum of ATP13A2-associated neurological disorders, which are commonly hallmarked by lysosomal and mitochondrial dysfunction. The disease presentation in our patients with hereditary spastic paraplegia was dominated by an adult-onset lower-limb predominant spastic paraparesis. Cognitive impairment was present in most of the cases and ranged from very mild deficits to advanced dementia with fronto-temporal characteristics. Nerve conduction studies revealed involvement of the peripheral motor and sensory nerves. Only one of five patients with hereditary spastic paraplegia showed clinical indication of extrapyramidal involvement in the form of subtle bradykinesia and slight resting tremor. Neuroimaging cranial investigations revealed pronounced vermian and hemispheric cerebellar atrophy. Notably, reduced striatal dopamine was apparent in the brain of one of the patients, who had no clinical signs or symptoms of extrapyramidal involvement.

Hereditary spastic paraplegia is a novel phenotype for germline de novo ATP1A1 mutation

“…Even before ATP1A1 , the pleiotropic effect of mutations in the Na + , K + ‐ATPase proteins had been found for ATP1A3 , that in the nervous system is exclusively expressed in neurons and whose mutations cause alternating hemiplegia of childhood, rapid‐onset dystonia‐parkinsonism, CAPOS syndrome and overlapping phenotypes and to a less extent for ATP1A2 , whose mutations cause familial hemiplegic or basilar migraine . Moreover, recessive mutations in ATP13A2 , a lysosomal P5‐type transport ATPase, involved in cellular protection from heavy metal ions, α‐synuclein, and mitochondrial toxicity, may cause a spectrum of pyramidal‐extrapyramidal degenerative disorders ranging from Kufor‐Rakeb syndrome/PARK9, neuronal ceroid lipofuscinosis and spastic paraplegia type 78 …”

“…19 Moreover, recessive mutations in ATP13A2, a lysosomal P5-type transport ATPase, involved in cellular protection from heavy metal ions, α-synuclein, and mitochondrial toxicity, may cause a spectrum of pyramidal-extrapyramidal degenerative disorders ranging from Kufor-Rakeb syndrome/PARK9, neuronal ceroid lipofuscinosis and spastic paraplegia type 78. 20 The term "inherited axonopathies" refers to disorders with lengthdependent axonal degeneration as CMT type 2 (ie, axonal type) and HSP. 21 Recently, it has been demonstrated how CMT2 and HSP disease proteins are significantly more linked than expected.…”

Overcoming the divide between ataxias and spastic paraplegias: Shared phenotypes, genes, and pathways

“…Some exemplary clusters of shared or interacting pathways underlying ASS diseases are: Phospholipid metabolism , including the genes PNPLA6 , 12,40,41 PLA2G6, DDHD1 (SPG 28), DDHD2 (SPG54 42 ), CYP2U1 (SPG49), and ABHD12 43 (for further overview, see references 40 and 44 ). Sphingolipid metabolism , including the genes FA2H , 15 GBA2 , 33,45 GALC, HEXA, ASA, PSAP , and GLB1 . Autophagy-lysosomal activity , including the genes SPG15 , SPG11 , 46,47 ATP13A2 (SPG78), 48,49 NPC1 , and NPC2 disease. 50-55 …”

“…Autophagy-lysosomal activity , including the genes SPG15 , SPG11 , 46,47 ATP13A2 (SPG78), 48,49 NPC1 , and NPC2 disease. 50-55 …”

Whole‐exome sequencing for variant discovery in blepharospasm

“…Less deleterious synonymous (CADD_phred = 17.53) and missense (CADD_phred = 21.1) variants were found in subjects 10076 and 25069, respectively (Table , Data ). Recessive mutations in ATP13A2 have been linked to Kufor–Rakeb syndrome (Ramirez et al., ) and spastic paraplegia 78 (Estrada‐Cuzcano et al., ), both of which may include dystonia as a clinical manifestation. Variants in ATP13A2 may also contribute to oligogenic inheritance in PD (Lubbe et al., ).…”