Mutations in CAPN1 Cause Autosomal-Recessive Hereditary Spastic Paraplegia

Abstract

Hereditary spastic paraplegia (HSP) is a genetically and clinically heterogeneous disease characterized by spasticity and weakness of the lower limbs with or without additional neurological symptoms. Although more than 70 genes and genetic loci have been implicated in HSP, many families remain genetically undiagnosed, suggesting that other genetic causes of HSP are still to be identified. HSP can be inherited in an autosomal-dominant, autosomal-recessive, or X-linked manner. In the current study, we performed whole-exome sequencing to analyze a total of nine affected individuals in three families with autosomal-recessive HSP. Rare homozygous and compound-heterozygous nonsense, missense, frameshift, and splice-site mutations in CAPN1 were identified in all affected individuals, and sequencing in additional family members confirmed the segregation of these mutations with the disease (spastic paraplegia 76 [SPG76]). CAPN1 encodes calpain 1, a protease that is widely present in the CNS. Calpain 1 is involved in synaptic plasticity, synaptic restructuring, and axon maturation and maintenance. Three models of calpain 1 deficiency were further studied. In Caenorhabditis elegans, loss of calpain 1 function resulted in neuronal and axonal dysfunction and degeneration. Similarly, loss-of-function of the Drosophila melanogaster ortholog calpain B caused locomotor defects and axonal anomalies. Knockdown of calpain 1a, a CAPN1 ortholog in Danio rerio, resulted in abnormal branchiomotor neuron migration and disorganized acetylated-tubulin axonal networks in the brain. The identification of mutations in CAPN1 in HSP expands our understanding of the disease causes and potential mechanisms.

Novel CAPN1 mutations extend the phenotypic heterogeneity in combined spastic paraplegia and ataxia

“…3 Recently, loss-of-function mutations in the CAPN1 gene have been described as causative for spastic paraplegia 76 (SPG76). 5 CAPN1 encodes a neutral calcium-activated protease known as calpain-1 protein, which is involved in processes of synaptic plasticity, neuronal migration, neuronal maintenance and necrosis, among others. 6 Calpain-1 contains three functional domains, including a protease domain, a C2-like (C2L) Ca 2+ binding domain, and a penta-EF-hand (PEF) Ca 2+ binding domain.…”

“…7,8 Notoriously, HSP patients with autosomal recessive inheritance showed higher clinical complexity, especially due to ataxia resulting in ataxiaspasticity spectrum. 9 Even though mutations in CAPN1 were initially associated with cerebellar ataxia in dogs and humans, 6,10 as well as in human complicated form HSP presented with any of ataxia, dysarthria and amyotrophy, 5 reports of pure form HSP patients with CAPN1 mutations are increasing. [11][12][13][14][15][16][17][18][19][20][21][22][23][24] Given this broad range of symptoms and contributing factors, it remains an ongoing challenge to find a specific, reliable correlation between genotype and phenotype for this disease complex.…”

Clinical features and genotype-phenotype correlation analysis in patients with ATL1 mutations: A literature reanalysis

“…Genetic mutations are the main cause of HSPs and there are currently over 72 spastic paraplegia genes or genetic loci (designated SPG1-SPG72 genetic type in order of their discovery) in which mutations can occur [3]. HSPs can be inherited as autosomal dominant (AD), autosomal recessive (AR) or X-linked trait or a spastic paraplegia syndrome.…”

Swimming in Deep Water: Zebrafish Modeling of Complicated Forms of Hereditary Spastic Paraplegia and Spastic Ataxia

“…Moreover, the authors injected the capn1a-MO in the Tg(islet1::GFP) zebrafish line expressing the green fluorescent protein (GFP) in the motor neurons, including the branchiomotor neurons. Capn1a deficiency resulted in abnormal branchiomotor neuron migration and disorganized axonal networks in the brain, supporting a neuroprotective role of calpain 1 (Gan-Or et al, 2016). This work opened up new avenues for expanding our knowledge about the role and effects of the different calpains on neurodegeneration and neuroprotection, and thus for furthering our understanding of the CAPN1-associated HSP phenotypes.…”