Skip to main page content
U.S. flag

An official website of the United States government

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Oct;7(10):1862-1869.
doi: 10.1002/acn3.51169. Epub 2020 Aug 29.

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

Affiliations

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

Lu-Lu Lai et al. Ann Clin Transl Neurol. 2020 Oct.

Abstract

Objective: Recessive mutations in the CAPN1 gene have recently been identified in spastic paraplegia 76 (SPG76), a complex hereditary spastic paraplegia (HSP) that is combined with cerebellar ataxia, resulting in an ataxia-spasticity disease spectrum. This study aims to assess the influence of CAPN1 variants on the occurrence of SPG76 and identify factors potentially contributing to phenotypic heterogeneity.

Methods: We screened a cohort of 240 unrelated HSP families for variants in CAPN1 using high-throughput sequencing analysis. We described in detail the clinical and genetic features of the SPG76 patients in our cohort and summarized all reported cases.

Results: Six unreported CAPN1-associated families containing eight patients with or without cerebellar ataxia were found in our cohort of HSP cases. These patients carried three previously reported homozygous truncating mutations (p.V64Gfs* 103, c.759+1G>A, and p.R285* ), and three additional novel compound heterozygous missense mutations (p.R481Q, p.P498L, and p.R618W). Lower limbs spasticity, hyperreflexia, and Babinski signs developed in about 94% of patients, with ataxia developing in 63% of cases. In total, 33 pathogenic mutations were distributed along the three reported functional domains of calpain-1 protein, encoded by CAPN1, with no hotspot region. A comparison of gender distribution between the two groups indicated that female SPG76 patients were significantly more likely to present with complicated HSP than male patients (P = 0.015).

Interpretation: Our study supports the clinically heterogeneous inter- and intra-family variability of SPG76 patients, and demonstrates that gender and calpain-1 linker structure may contribute to clinical heterogeneity in SPG76 cases.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
Mutational spectrum of CAPN1 in SPG76 patients. (A) The pedigrees of six SPG76 families in our cohort, with CAPN1 mutations indicated. Filled black squares and circles indicate affected individuals. The proband in each family is indicated by an arrow. The genotypes of all available family members were determined. Dash symbol indicates reference allele. (B) The mutation distribution across the CAPN1 gene and corresponding calpain‐1 protein containing a protease domain (amino acid 56‐352), a C2L Ca2+‐binding domain (amino acid 364‐524), and a PEF Ca2+‐binding domain (amino acid 546‐714). Gray bars indicate the linker structure. Filled green circles highlight the mutations causing pure form HSP. Filled red circles highlight the mutations causing complicated form HSP. The half‐red and half‐green circles highlight the mutations causing either pure or complicated form HSP. (C) Statistical analysis of the correlation between mutation distribution and HSP forms.
Figure 2
Figure 2
Comprehensive analysis of phenotypic heterogeneity for CAPN1‐associated SPG76. (A) Distribution of pure, complicated, and undetermined forms (no available clinical information) across all reported SPG76 patients (n = 67). (B) Statistical comparison of the percentage of parental kinship between the pure and complicated forms of SPG76. Chi‐squared followed by Bonferroni test. (C) Statistical comparison of the gender distribution between pure and complicated forms. Chi‐squared followed by Bonferroni test. * indicates P < 0.025. (D) Statistical comparison of the age at onset between pure and complicated forms. Student’s t‐test. (E) Statistical comparison of the disease duration between pure and complicated forms. Student’s t‐test. (F) Statistical comparison of the percentage of truncating or missenses mutation types between pure and complicated forms. Nonsense, frameshift, and splicing site mutations are combined into the truncating mutation category for comparison with missense mutations. In box and whisker plots, error bars indicate min to max. Chi‐squared followed by Bonferroni test. ns, not significant.

Similar articles

Cited by

References

    1. Fink JK, Heiman‐Patterson T, Bird T, et al. Hereditary spastic paraplegia: advances in genetic research. Hereditary Spastic Paraplegia Working group. Neurology 1996;46:1507–1514. 10.1212/wnl.46.6.1507. - DOI - PubMed
    1. Fink JK. Hereditary spastic paraplegia: clinico‐pathologic features and emerging molecular mechanisms. Acta Neuropathol 2013;126(3):307–328. 10.1007/s00401-013-1115-8. - DOI - PMC - PubMed
    1. Shribman S, Reid E, Crosby AH, et al. Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches. Lancet Neurol 2019;18:1136–1146. 10.1016/S1474-4422(19)30235-2. - DOI - PubMed
    1. Vaz FM, McDermott JH, Alders M, et al. Mutations in PCYT2 disrupt etherlipid biosynthesis and cause a complex hereditary spastic paraplegia. Brain 2019;142:3382–3397. 10.1093/brain/awz291. - DOI - PMC - PubMed
    1. Gan‐Or Z, Bouslam N, Birouk N, et al. Mutations in CAPN1 cause autosomal‐recessive hereditary spastic paraplegia. Am J Hum Genet 2016;98:1038–1046. 10.1016/j.ajhg.2016.04.002. - DOI - PMC - PubMed

Publication types

Supplementary concepts

Grants and funding

This work was funded by National Natural Science Foundation of China grants 81771230, 81801130, and U1905210; Joint Funds for the Innovation of Science and Technology of Fujian Province grants 2017Y9094 and 2018Y9082; Key Clinical Specialty Discipline Construction Program of Fujian grant ; Natural Science Foundation of Fujian Province grant 2019J05076; Startup Fund for scientific research of Fujian Medical University grants 2017XQ1072 and 2018QH2033.

LinkOut - more resources