This report describes spastic paraplegia 76 (SPG76), which is a subtype of spastic paraplegia; SPG76 is inherited as an autosomal recessive. The human gene implicated in this disease is calpain 1 (CAPN1) which encodes one of many calpains (calcium-activated proteases) in humans. There are two Drosophila orthologs, CalpB and CalpA, for which classical amorphic alleles, RNAi-targeting constructs and alleles caused by insertional mutagenesis have been generated.
A UAS construct of the wild-type human gene Hsap\CAPN1 has been introduced into flies, but has not been characterized.
Neither CalpB nor CalpA is an essential gene in flies: animals homozygous for amorphic mutations of either are viable and fertile. CalpB is implicated in normal cell migration. Neuronal knockdown of CalpB effected by RNAi results in progressive locomotor defects. A knockout allele of CalpB results in locomotor deficits, increased unfolded protein response (UPR) activation, and increased apoptosis. CalpA appears to play a role in myoblast fusion. Overexpression of CalpA in muscle cell progenitors results in partial embryonic lethality; overexpression in transverse muscles allows survival to larval stages, but results in impaired locomotor behavior. Several physical and genetic interactions for both fly genes have been reported; see below and in the gene reports for CalpB and CalpA.
[updated July 2026 by FlyBase; FBrf0222196]
The hereditary spastic paraplegias (SPG, HSP) are a large group of clinically and genetically diverse disorders characterized by progressive, usually severe, lower extremity spasticity and weakness. SPG is classified by mode of inheritance (autosomal dominant, autosomal recessive, and X-linked) and whether the primary symptoms occur in isolation ('uncomplicated SPG') or with other neurologic abnormalities ('complicated SPG'). [from MIM:182600; 15.06.29]
[SPASTIC PARAPLEGIA 76, AUTOSOMAL RECESSIVE; SPG76](https://omim.org/entry/616907)
[CALPAIN 1; CAPN1](https://omim.org/entry/114220)
See general description of spastic paraplegia above. SPG76 is characterized by young-adult onset of slowly progressive spasticity of the lower limbs resulting in gait difficulties. Most affected individuals have upper limb involvement and additional features such as foot deformities and dysarthria. [from MIM:616907; 2017.03.03]
Autosomal recessive hereditary spastic paraplegia-76 (SPG76) is caused by homozygous or compound heterozygous mutation in the CAPN1 gene (autosomal recessive). [from MIM:616907; 2017.03.03]
Cultured fibroblasts derived from human SPG76 patients exhibit increased unfolded protein response (UPR) activation, increased apoptosis and cell death (Brivo, et al., 2026, pubmed:41620148).
The calpains, calcium-activated neutral proteases, are non-lysosomal, intracellular cysteine proteases. The mammalian calpains include ubiquitous, stomach-specific, and muscle-specific proteins. CAPN1 encodes the large subunit of the ubiquitous enzyme, calpain 1. [Gene Cards; CAPN1; 2017.03.03]
Calpain (calcium-dependent protease) is an intracellular protease that requires calcium for its catalytic activity. [from MIM:114220; 2017.03.03]
Many to many (multiple human to 2 Drosophila).
High- to moderate-scoring ortholog of human CAPN9, CAPN2, CAPN1, CAPN3, CAPN8, and others (2 Drosophila to multiple human). CalpB shares 44-45% identity and 62-64% similarity with CAPN9, CAPN2, and CAPN1.
High- to moderate-scoring ortholog of human CAPN9, CAPN8, CAPN2, CAPN1, CAPN3, and others (2 Drosophila to multiple human). CalpA shares 41-44% identity and 57-60% similarity with CAPN9, CAPN8, CAPN2, and CAPN1.
