Alternative titles; symbols
HGNC Approved Gene Symbol: SPG7
Cytogenetic location: 16q24.3 Genomic coordinates (GRCh38) : 16:89,508,388-89,557,768 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q24.3 | Spastic paraplegia 7, autosomal recessive | 607259 | Autosomal dominant; Autosomal recessive | 3 |
The SPG7 gene encodes paraplegin, a component of the m-AAA protease. The m-AAA protease is an ATP-dependent proteolytic complex of the mitochondrial inner membrane that degrades misfolded proteins and regulates ribosome assembly (Koppen et al., 2007).
Based on linkage analysis of a family with autosomal recessive spastic paraplegia that mapped to 16q24.3 (SPG7; 607259), Casari et al. (1998) used an EST clone to screen a human cDNA library and isolate a candidate gene. The full-length cDNA sequence corresponding to this gene encoded a deduced 795-amino acid protein, which they named paraplegin. Northern blot analysis detected a transcript of approximately 3.2 kb in all fetal and adult tissues tested. Two additional hybridizing transcripts of approximately 2.6 and 7.5 kb were detected in heart and pancreas.
Casari et al. (1998) concluded that the CAR gene identified by Pullman and Bodmer (1992) as a 459-bp transcript colinear with genomic DNA is part of the 3-prime untranscribed region of the SPG7 gene. Among other evidence supporting their conclusion, Casari et al. (1998) found a sequence 100% identical to the CAR sequence in over 30 different SPG7 clones, including ESTs, identified from many different cDNA libraries.
Settasatian et al. (1999) determined that the SPG7 gene contains 17 exons, ranging from 78 to 242 bp, and spans approximately 52 kb. The exon/intron boundaries and all splice junctions are consistent with consensus sequences for donor and acceptor sites.
By genetic linkage analysis using a TaqI polymorphism in CEPH families, Koyama et al. (1993) demonstrated that CAR is close to D16S7 and D16S154, which are located in the 'peritelomeric' region of 16q. Mangion et al. (1999) stated that the CMAR gene maps to 16q24.3.
By positional cloning, De Michele et al. (1998) identified the SPG7 gene within the 16q24.3 critical region for autosomal recessive spastic paraplegia-7 (607259).
Pullman and Bodmer (1992) suggested that the CAR gene encodes an adhesion signal transduction molecule that functions in the suppression of tumor invasion. Casari et al. (1998) presented data calling this functional information into question.
Casari et al. (1998) determined that paraplegin is highly homologous to the yeast mitochondrial ATPases AFG3, RCA1, and YME1 (see 607472), which have both proteolytic and chaperone-like activities at the inner mitochondrial membrane. Immunofluorescence analysis and import experiments showed that paraplegin localizes to mitochondria. Analysis of muscle biopsies from 2 patients with paraplegin mutations showed typical signs of mitochondrial OXPHOS defects, thus suggesting a mechanism for neurodegeneration in SPG-type disorders.
Consistent with a role for paraplegin in mitochondrial function, muscle biopsies obtained from some patients with SPG7 mutations showed typical signs of mitochondrial disease (Casari et al., 1998). These included ragged-red fibers, intense succinate dehydrogenase-stained areas, and cytochrome oxidase-negative fibers. Furthermore, the degree of mitochondrial abnormality correlated with the severity of the disease. Taken together, these findings suggested that a mitochondrial-based mechanism underlies spastic paraplegia-7. Crosby and Proukakis (2002) cited preliminary reports of electron microscopy studies in mice lacking paraplegin that revealed that, long before degeneration, the axons were filled with abnormal mitochondria. Subsequently, swollen axons containing accumulated organelles and neurofilaments were seen, which suggested that mitochondrial dysfunction may lead to axonal degeneration by impairing axonal transport. Crosby and Proukakis (2002) concluded that aberrant cellular trafficking dynamics appears to be a common process responsible for the pattern of neurodegeneration seen in hereditary spastic paraplegia.
Using in vitro protein binding assays and immunoprecipitation analysis, Koppen et al. (2007) showed that paraplegin interacted with AFG3L2 (604581) in the m-AAA protease complex. Paraplegin did not interact with itself. Loss of paraplegin in Spg7 -/- mice or in SPG7 patient fibroblasts resulted in m-AAA protease complexes made up of only homodimerized AFG3L2 that were proteolytically active in yeast complementation assays. Bonn et al. (2010) used the yeast complementation assay to evaluate the functional consequences of pathogenic mutations (see, e.g., 602783.0010 and 602783.0011) in the SPG7 gene.
Casari et al. (1998) found that all affected individuals from the SPG7 family reported by De Michele et al. (1998) were homozygous for a 9.5-kb deletion (602783.0003) in the SPG7 gene. In 2 additional unrelated families with autosomal recessive SPG, 1 demonstrating a pure form of the disorder and 1 demonstrating a complicated form of the disorder, Casari et al. (1998) identified 2 additional homozygous paraplegin mutations (602783.0001-602783.0002), both resulting in a frameshift and a truncated protein.
Koyama et al. (1993) identified an insertion/deletion polymorphism in the coding region of the CMAR gene; the variant was detected in 9 chromosomes among 30 unrelated Japanese individuals. Durbin et al. (1994) detected a 4-bp insertion (CACA) at nucleotide 241 of the CMAR gene. Casari et al. (1998) noted that the polymorphisms identified by Koyama et al. (1993) and Durbin et al. (1994) would result in major changes in the CMAR putative protein product, suggesting that the original CMAR cDNA clone may not encode a protein in vivo and that functional data obtained using CMAR cDNA in transfection experiments may be due to artifactual translation of a peptide encoded by the CMAR sequence.
In 1 (0.7%) of 136 index patients with autosomal recessive SPG, Elleuch et al. (2006) identified 2 mutations in the SPG7 gene (602783.0004-602783.0005). Twenty families had at least 1 variant in the SPG7 gene that was not found in 550 control chromosomes. In 4 of these families, mutations were predicted to be highly deleterious, suggesting that they may have contributed to the phenotype. The authors identified several additional rare variants in the SPG7 gene, which were of undetermined significance.
Arnoldi et al. (2008) identified 7 different SPG7 mutations (see, e.g., 602783.0007-602783.0009) in 6 (4.4%) of 135 Italian patients with spastic paraplegia. Four of the patients were heterozygous for the mutations, which fell within conserved domains of the protein and were not found in controls.
Sanchez-Ferrero et al. (2013) sequenced the SPG7 gene in 285 Spanish patients with spastic paraplegia who were negative for mutations in the SPG4 (604277) and SPG3A (606439) genes. Fourteen SPG7 mutations, including 12 novel mutations, were identified in 14 patients. The mutations included 2 large deletions, 5 missense changes, 4 nonsense mutations, 2 frameshift insertion/deletions, and 1 splice site mutation. Thirteen patients had only a single heterozygous mutation, suggesting a dominant effect for some SPG7 mutations. Functional studies were not performed to assess the biologic significance. An A510V substitution (602783.0012) was found in 8 patients (3%): 4 carried A510V in compound heterozygous state with another SPG7 mutation, 1 was homozygous for A510V, and 3 patients were heterozygous for A510V. The A510V substitution was also identified in 1% of controls. All patients had adult onset of the disorder, but only 35% had a complicated phenotype.
In a 57-year-old man, born to first-cousin Caucasian parents, with childhood optic nerve atrophy and SPG7, Eriksen et al. (2022) identified a homozygous mutation in the SPG7 gene (M1?; 602783.0013), which alters the start codon and is expected to abolish production of paraplegin. The patient had onset of vision loss at age 6 years, but findings of spastic paraplegia were subtle and the diagnosis was not suspected until the likely pathogenic variant in the SPG7 gene was identified. The authors noted that the SPG7 gene should be added to the workup of suspected hereditary optic neuropathy.
Exclusion Studies
Because the SPG7 gene was mapped to chromosome 16q24.3, a region of frequent loss of heterozygosity (LOH) in sporadic breast and prostate cancer, Settasatian et al. (1999) performed SSCP analysis of 10 exons of this gene in a number of sporadic breast cancer samples showing LOH at 16q24.3. No mutations were detected; only SNPs were observed in 1 exon and 3 introns.
Ferreirinha et al. (2004) developed a mouse model for autosomal recessive hereditary spastic paraplegia due to mutation in the SPG7 gene, which encodes the mitochondrial ATPase paraplegin. Paraplegin-deficient mice were affected by a distal axonopathy of spinal and peripheral axons, characterized by axonal swelling and degeneration. Ferreirinha et al. (2004) found that mitochondrial morphologic abnormalities occurred in synaptic terminals and in distal regions of axons long before the first signs of swelling and degeneration and correlated with onset of motor impairment. Axonal swellings occurred through massive accumulation of organelles and neurofilaments, suggesting impairment of anterograde axonal transport. Retrograde axonal transport was delayed in symptomatic mice. Ferreirinha et al. (2004) speculated that local failure of mitochondrial function may affect axonal transport and cause axonal degeneration. They concluded that a timely therapeutic intervention might prevent the loss of axons.
In Spg7-null mice, Pirozzi et al. (2006) found that intramuscular delivery of adeno-associated virus vector containing Spg7 halted the progression of neuropathologic changes and rescued disease-associated morphologic changes in the mitochondria of peripheral nerves. A single injection before onset of symptoms improved motor performance of mice for up to 10 months, suggesting that peripheral neuropathy contributes to the clinical phenotype.
Martinelli et al. (2009) reported an early-onset severe neurologic phenotype in Spg7-null/Afg3l2 +/- double-mutant mice characterized by loss of balance, tremor, and ataxia. Double-mutant mice displayed acceleration and worsening of the axonopathy observed in Spg7-null mice. In addition, they showed prominent cerebellar degeneration with loss of Purkinje cells and parallel fibers, and reactive astrogliosis. Mitochondria from affected tissues were prone to lose mtDNA and had unstable respiratory complexes. At late stages, neurons contained structural abnormal mitochondria defective in COX-SDH reaction. Martinelli et al. (2009) suggested that different neuronal populations may have variable thresholds of susceptibility to reduced levels of the m-AAA protease, and that impaired mitochondrial proteolysis may be a mechanism of cerebellar degeneration.
In 1 of 2 brothers from a small village in southern Italy who had autosomal recessive hereditary pure spastic paraplegia (SPG7; 607259), Casari et al. (1998) identified a 2-bp deletion (784del2) in the SPG7 gene. This mutation causes a frameshift that abolishes approximately 60% of the protein. The patient, who showed typical signs of pure SPG with an age of onset of 26 years, was homozygous for this mutation; consanguinity was very likely. The other brother was unavailable for study.
Casari et al. (1998) found a mutation in the SPG7 gene in a French family in which complicated SPG segregated as an autosomal recessive trait (SPG7; 607259). Patients from this family were affected by a form of SPG with a mean age of onset of 34 years. They showed progressive weakness and spasticity of the lower limbs, decreased perception of sharp stimulation, diminished vibratory sense, and urinary incontinence, which are typical signs of SPG. These patients also had optic atrophy (3 of 3 examined), cortical atrophy (1 of 3 examined), and cerebellar atrophy (2 of 3 examined). All affected sibs from this family were homozygous for an A insertion at position 2228 of the paraplegin cDNA, while their mother was heterozygous for the same mutation. This insertion creates a frameshift and a stop codon only 2 amino acids downstream, resulting in a truncated form of paraplegin that is missing 57 amino acids at the C terminus.
Casari et al. (1998) found that all affected individuals from the family with autosomal recessive spastic paraplegia-7 (SPG7; 607259) reported by De Michele et al. (1998) were homozygous for a 9.5-kb deletion in the SPG7 gene.
In 4 affected sibs of a Moroccan family with autosomal recessive spastic paraplegia-7 (SPG7; 607259), Elleuch et al. (2006) identified compound heterozygosity for 2 mutations in the SPG7 gene. One allele had a 2-bp deletion and 1-bp insertion (850delTTinsC), resulting in premature termination of the protein. The second allele had an in-frame deletion (1742delTGG; 602783.0005), resulting in the deletion of val581.
For discussion of the in-frame deletion in the SPG7 gene (1742delTGG) that was found in compound heterozygous state in sibs with autosomal recessive spastic paraplegia-7 (SPG7; 607259) by Elleuch et al. (2006), see 602783.0004.
In 3 sibs, born of consanguineous Turkish parents, with complicated spastic paraplegia-7 (SPG7; 607259), Warnecke et al. (2007) identified a homozygous 2075G-C transversion in exon 15 of the SPG7 gene, resulting in a ser692-to-thr (S692T) substitution. Age at onset ranged between 10 and 25 years, with lower limb spasticity, hyperreflexia, and cerebellar dysarthria. Unusual features included cognitive defects in executive function and attention, and supranuclear palsy. White matter abnormalities were evident in the spinal cord, frontal lobe, and midbrain.
In 3 affected individuals from 2 presumably unrelated Italian families with autosomal recessive spastic paraplegia-7 (SPG7; 607259), Arnoldi et al. (2008) identified a homozygous 233T-A transversion in exon 2 of the SPG7 gene, resulting in a leu78-to-ter (L78X) substitution. Haplotype analysis indicated a founder effect. All patients had adult onset of lower limb weakness and gait instability with relatively mild spasticity. One patient had mild cerebellar signs, and another had bladder dysfunction. Two sibs had mild cognitive deficits. Skeletal muscle biopsy of 1 patient showed ragged-red fibers, but detailed analysis of mitochondrial respiratory functions in all 3 patients showed a mild and heterogeneous patterns of dysfunction, excluding a specific defect.
In an Italian patient with autosomal recessive spastic paraplegia-7 (SPG7; 607259), Arnoldi et al. (2008) identified compound heterozygosity for 2 mutations in the SPG7 gene: a 1-bp deletion (1616delC) and a 5.1-kb deletion (602783.0009).
In an Italian patient with autosomal recessive spastic paraplegia-7 (SPG7; 607259), Arnoldi et al. (2008) identified compound heterozygosity for 2 mutations in the SPG7 gene: a 5.1-kb deletion, resulting in the deletion of exons 11, 12, and 13, and a 1-bp deletion (1616delC; 602783.0008). The 5.1-kb deletion appeared to be mediated by short interspersed nuclear element (SINE) retrotransposons.
In 2 sibs with autosomal recessive spastic paraplegia-7 (SPG7; 607259), Bonn et al. (2010) identified compound heterozygosity for 2 mutations in the SPG7 gene: a 1045G-A transition in exon 8, resulting in a gly349-to-ser (G349S) substitution, and a 1749G-C transversion in exon 13, resulting in a trp583-to-cys (W583C; 602783.0011) substitution. The G349S mutation was found in 5 (0.7%) of 756 controls, and the W583C mutation was not found in 756 controls. In vitro complementation assay using mAAA protease-deficient yeast showed that the G349S and W583C variants had impaired proteolytic function.
For discussion of the trp583-to-cys (W583C) mutation in the SPG7 gene that was found in compound heterozygous state in 2 sibs with autosomal recessive spastic paraplegia-7 (SPG7; 607259) by Bonn et al. (2010), see 602783.0010.
In 8 Spanish probands with autosomal recessive spastic paraplegia-7 (SPG7; 607259), Sanchez-Ferrero et al. (2013) identified a 1529C-T transition in the SPG7 gene, resulting in an ala510-to-val (A510V) substitution at a highly conserved residue (rs61755320). Four patients carried the mutation in compound heterozygous state with another pathogenic mutation in the SPG7 gene, 1 patient was homozygous for A510V, and 3 patients carried A510V as a single heterozygous mutation. In the whole cohort, A510H was present in 8 (3%) of 285 Spanish patients with spastic paraplegia compared to 1% of controls. The findings suggested that A510H likely contributes to the pathogenesis of SPG7. Sanchez-Ferrero et al. (2013) noted that although A510V had initially been reported as a rare polymorphism, yeast complementation assays by Bonn et al. (2010) showed that this missense change would perturb the proteolytic function of the heterooligomeric m-AAA protease.
In a 57-year-old man, born to first-cousin Caucasian parents, with childhood optic nerve atrophy and spastic paraplegia-7 (SPG7; 607259), Eriksen et al. (2022) identified a homozygous c.2T-G transversion (c.2T-G, NM_003119.4) in the SPG7 gene, which alters the start codon (Met1?) and is expected to abolish production of paraplegin. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database (v2.1.1). Segregation analysis was not reported. The patient had onset of vision loss at age 6 years, but findings of spastic paraplegia were subtle and the diagnosis was not suspected until the likely pathogenic variant in the SPG7 gene was identified.
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