A novel CPT1C variant causes pure hereditary spastic paraplegia with benign clinical course

Abstract

Hereditary spastic paraplegia 73 (SPG73) was currently identified in only one family with variant in the neuronal isoform of carnitine palmitoyl-transferase 1C (CPT1C) gene. We described a new family, in which affected individuals exhibited pure hereditary spastic paraplegia with benign clinical course. Exome sequencing revealed a novel nonsense variant in the CPT1C gene. The level of CPT1C mutant transcript significantly decreased compared to that of wild-type transcript, and can be recovered after cycloheximide administration, which indicated that nonsense-mediated mRNA decay was a mechanism that might be responsible for the phenotype. Our findings expanded the clinical and genetic spectrum of SPG73.

Figure 1

The clinical and genetic data in the SPG73 family. The family tree indicated an autosomal dominant inherited pattern (A, arrow indicates index patient). The chromagram revealed a variant (c.226C>T) in the CPT1C gene (B). The novel variant (red font) caused a premature stop in exon 3 of the CPT1C gene, the reported variant (black font) was also located in the exon 3 (C). CPT1C protein is composed of a small N‐terminal regulatory domain (NRD, 1‐47) and a large catalytic‐terminal domain (171‐803), separated by two transmembrane (TM) domains and a short connecting loop (D).

Figure 2

The pathogenic investigations of mutant CPT1C. The GFP fluorescence showed a normal expression in 293T cells transfected with pEGFP‐N1 vectors (A), an increased expression in 293T cells transfected with wild‐type pEGFP‐N1‐CPT1C vectors (B), and a significantly decreased expression in 293T cells transfected with c.226C>T mutant pEGFP‐N1‐CPT1C vectors (C). After administration of cycloheximide (CHX), the expression of mutant CPT1C was recovered (D). Quantitative PCR measurements showed a significant reduction in the mutant CPT1C transcript expression compared to the level of wild‐type transcript. Repeated three times for every test. Data were analyzed by one‐way ANOVA test; Error bars are SEM; *P < 0.01(E). Immunoblot showed that no full‐length or truncated CPT1C proteins were detected in the mutant cells (F).