Clinical and genetic characterization of NIPA1 mutations in a Taiwanese cohort with hereditary spastic paraplegia

Abstract

Objective NIPA1 mutations have been implicated in hereditary spastic paraplegia (HSP) as the cause of spastic paraplegia type 6 (SPG6). The aim of this study was to investigate the clinical and genetic features of SPG6 in a Taiwanese HSP cohort. Methods We screened 242 unrelated Taiwanese patients with HSP for NIPA1 mutations. The clinical features of patients with a NIPA1 mutation were analyzed. Minigene‐based splicing assay, RT‐PCR analysis on the patients' RNA, and cell‐based protein expression study were utilized to assess the effects of the mutations on splicing and protein expression. Results Two patients were identified to carry a different heterozygous NIPA1 mutation. The two mutations, c.316G>A and c.316G>C, are located in the 3′ end of NIPA1 exon 3 near the exon–intron boundary and putatively lead to the same amino acid substitution, p.G106R. The patient harboring NIPA1 c.316G>A manifested spastic paraplegia, epilepsy and schizophrenia since age 17 years, whereas the individual carrying NIPA1 c.316G>C had pure HSP since age 12 years. We reviewed literature and found that epilepsy was present in multiple individuals with NIPA1 c.316G>A but none with NIPA1 c.316G>C. Functional studies demonstrated that both mutations did not affect splicing, but only the c.316G>A mutation was associated with a significantly reduced NIPA1 protein expression. Interpretation SPG6 accounted for 0.8% of HSP cases in the Taiwanese cohort. The NIPA1 c.316G>A and c.316G>C mutations are associated with adolescent‐onset complex and pure form HSP, respectively. The different effects on protein expression of the two mutations may be associated with their phenotypic discrepancy.

The Role of Thickened Nuchal Translucency on Copy Number Variations and Pregnancy Outcomes in Northeast Coast of Fujian Province, China: A Comparison Between Traditional Karyotyping and Single Nucleotide Polymorphism Array Analysis

“…The 0.5 Mb 15q11.2 deletion, deleted TUBGCP5, NIPA1, and BP1-BP2 within the 15q11.2 region. Heterozygous mutations in NIPA1 are associated with autosomal dominant spastic truncations spastic paraplegia 6 [32,33]. A previous study estimated the penetrance of this fragment deletion to be approximately 10.4%, suggesting an incomplete penetrance or expressivity difference [34].…”

Characterization of a novel TFG variant causing autosomal recessive pure hereditary spastic paraplegia

“…Mutational analysis of TFG was conducted by utilizing a targeted sequencing panel covering 76 HSP genes and the 57 other genes implicated in diseases with an HSP‐like phenotype on an Illumina HiSeq2500 (Table S1 ). 10 Sequence variants within the targeted regions were called by aligning the sequenced reads to the reference Human Genome version 38 (hg38/GRCh38). The TFG variants were further confirmed through Sanger sequencing and named according to the reference TFG sequence (NM_006070.6).…”