Mutational spectrum of the SPAST and ATL1 genes in Korean patients with hereditary spastic paraplegia

https://doi.org/10.1016/j.jns.2015.07.024Get rights and content

Highlights

  • We conducted mutational analysis of the SPAST and/or ATL1 genes in 206 HSP patients.

  • We identified 34 SPAST pathogenic variants and 3 ATL1 pathogenic variants in 52 patients.

  • Our study suggests that other genes may be involved in HSP in the Korean population.

Abstract

Hereditary spastic paraplegia (HSP) is a genetically heterogeneous group of diseases characterized by insidiously progressive lower-extremity weakness and spasticity. Spastic paraplegia 4 (SPAST) is the most common type of uncomplicated autosomal dominant HSP (40% of such cases), and spastic paraplegia 3A (ATL1) is the second most common. Here, we conducted mutational analysis of the SPAST and/or ATL1 genes in 206 unrelated patients with HSP. DNA sequencing and multiplex ligation-dependent probe amplification was used to analyze SPAST or ATL1 pathogenic variants. To confirm splice-site pathogenic variants, mRNA transcripts were analyzed by reverse transcription-polymerase chain reactions and sequencing. Among the 52 patients with medical records and SPAST or ATL1 gene pathogenic variants or novel unclassified variants, 50 showed spasticity or weakness in their lower extremities. We identified 16 known and 18 novel SPAST pathogenic variants and 2 known and a novel splicing pathogenic variants in ATL1. We also identified 4 unclassified SPAST variants in 5 patients and an unclassified ATL1 variant in 1 patient. Further, a novel leaky-splicing variant (c.1537-11A>G) was found in SPAST, which caused skipping of exon 13 or exons 13–14. Among the 206 unrelated patients with HSP, SPAST or ATL1 pathogenic variants and potentially pathogenic variants were identified in 52 patients, a low pathogenic variant rate compared to previous results. Results from our study suggest that other genes may be involved in HSP in the Korean population.

Introduction

Hereditary spastic paraplegia (HSP) is a genetically heterogeneous group of diseases characterized by insidiously progressive lower-extremity weakness and spasticity [1], [2]. Spastic paraplegia 4 (SPG4) is the single most common type of HSP, accounting for about 40% of such cases and spastic paraplegia 3A (SPG3A) is the second most common type of autosomal dominant HSP (AD-HSP) [3]. Other clinical features include lower extremity hyper-reflexia, extensor plantar responses, loss of vibration senses in both lower extremities, and voiding difficulties. These symptoms result from length-dependent axonal degeneration of the descending corticospinal tracts and the ascending dorsal columns [4]. HSP is classified as “complicated” or “pure,” depending on whether gait disturbance is accompanied by the respective presence of other symptoms, such as seizure, dementia, cognitive dysfunction cerebellar ataxia, or neuropathy. HSP can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. HSP is genetically heterogeneous, with 77 loci and 55 genes associated with HSP [5]. In autosomal dominant HSP, 11 loci and 19 HSP-related genes have been identified elsewhere [6].

The spastin protein consists of 616 amino acids and 4 major domains: a transmembrane domain, a microtubule-interacting and trafficking (MIT) domain, a microtubule-binding domain (MTBD), and an ATPase associated with various cellular activities (AAA) domain [7]. The SPAST gene product, spastin, associates with microtubules through its adenosine triphosphate binding domain associated with diverse cellular activities (AAA domain) [8], [9]. Altered spastin proteins are defective in their ability for normal microtubule interactions, which disrupts organelle transport and leads to the abnormal localization of intracellular organelles, such as mitochondria and peroxisomes [8], [10], [11]. The AAA domain (amino acids 342 to 599) regulates the function of the protein through an ATPase associated pathway, and this region is highly conserved between species. Most pathogenic variants affect the AAA domain, suggesting a possible loss of function of spastin in HSP [10].

Previous studies have identified more than 450 different SPAST variants and 56 ATL1 pathogenic variants (http://www.hgmd.cf.ac.uk/ac/index.php). A previous study with Korean HSP patients reported that the frequency of SPAST pathogenic variants in AD-HSP was 64% [12], which was higher than other reports [3], [6]. Therefore, the aim of this study was to screen for and analyze SPAST and/or ATL1 variants in 206 unrelated Korean HSP probands to better characterize SPAST and ATL1 variants in the Korean population.

Section snippets

Subjects

Two hundred and six unrelated patients were recruited for this study and referred for molecular analysis of HSP. SPAST variants were analyzed by direct sequencing of DNA samples from 185 patients, or by multiplex ligation-dependent probe amplification (MLPA) of DNA samples from 145 patients. Similarly, ATL1 variants were analyzed by sequencing DNA from 141 patients, or by MLPA analysis of DNA samples from 140 patients. A total of 117 patients were evaluated for pathogenic variants in both

Clinical aspects of HSP patients

Among the 52 patients with medical records who had pathogenic or novel variants within the SPAST or ATL1 genes, 50 patients showed one of these symptoms: spasticity or weakness in their lower extremities. Four patients had complicated symptoms, such as dysarthria and memory impairment. The age of disease onset ranged from 3 to 50. Among these 52 patients, 38 had a family history of HSP, 13 had sensory impairment of the lower extremities, and 9 had bladder-related symptoms (Table 1).

Mutational analysis of SPAST gene

Mutation

Discussion

Our study showed relatively lower frequency of SPAST and ATL1 pathogenic variants than previously Korean reports, which was reported 8 pathogenic variants in 18 unrelated patients (44%) and 7 pathogenic variant in 11 patients in AD-HSP (64%) [12]. It might be the difference of numbers of the patients. And we did not analyze other causative genes associated with HSP. The present study revealed that the frequency of exonic deletions was 21% and that of exonic duplications was 2% in HSP patients

Conflict of interest

The authors declare no conflict of interest.

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