Clinical features and genotype-phenotype correlation analysis in patients with ATL1 mutations: A literature reanalysis

Abstract

BackgroundThe hereditary spastic paraplegias (HSPs) are a group of clinically and genetically heterogeneous disorders. Approximately 10% of the autosomal dominant (AD) HSPs (ADHSPs) have the spastic paraplegia 3A (SPG3A) genotype which is caused by ATL1 gene mutations. Currently there are more than 60 reported ATL1 gene mutations and the genotype-phenotype correlation remains unclear. The study aims to investigate the genotype-phenotype correlation in SPG3A patients.MethodsWe performed a reanalysis of the clinical features and genotype-phenotype correlations in 51 reported studies exhibiting an ATL1 gene mutation.ResultsMost HSPs-SPG3A patients exhibited an early age at onset (AAO) of <10 years old, and showed an autosomal dominant pure spastic paraplegia. We found that 14% of the HSPs-SPG3A patients presented complicated phenotypes, with distal atrophy being the most common complicated symptom. The AAO of each mutation group was not statistically significant (P > 0.05). The mutational spectrum associated with ATL1 gene mutation is wide, and most mutations are missense mutations, but do not involve the functional motif of ATL1 gene encoded atlastin-1 protein.ConclusionsOur findings indicate that there is no clear genotype-phenotype correlation in HSPs-SPG3A patients. We also find that exons 4, 7, 8 and 12 are mutation hotspots in ATL1 gene.Electronic supplementary materialThe online version of this article (doi:10.1186/s40035-017-0079-3) contains supplementary material, which is available to authorized users.

Clinical and genetic characterization of a cohort of Chinese patients with hereditary spastic paraplegia

“…The current findings were consistent with the notion that mutations in SPAST , ATL1 , and REEP1 are the most common causes of autosomal dominant HSP. It has been reported that 10.56% of ATL mutation carriers show incomplete penetrance, and we believe modulator genes or other factors may influence the phenotype. The clinical features of patient with ATL1 c.1246C>T mutation is different with a previous report, in which the pedigree with this mutation had a late‐onset, mental impairment, and thin corpus callosum in brain MRI .…”

In vivo Analysis of CRISPR/Cas9 Induced Atlastin Pathological Mutations in Drosophila

“…Mutations in Atlastin-1 have been identified as the cause of SPG3A, an autosomal dominant form of hereditary spastic paraplegia (HSP; Zhao et al, 2001;Zhao and Liu, 2017). The HSPs are a group of clinically heterogeneous neurological disorders classified into "pure" or "complicated" on the basis of the clinical features (Blackstone, 2018;Shribman et al, 2019).…”

“…More than 60 different ATL1 gene mutations have been described, mostly missense mutations but also a limited number of small deletions, small insertions, splice site mutations, and whole exon deletions (Blackstone, 2018). Nevertheless, the genotype-phenotype correlation remains utterly unclear (Zhao and Liu, 2017).…”

Extensive In Silico Analysis of ATL1 Gene : Discovered Five Mutations That May Cause Hereditary Spastic Paraplegia Type 3A

“…It is primarily produced in the brain and the spinal cord in the central nervous system. In neurons, this protein is located mainly in the endoplasmic reticulum and it is responsible for endoplasmic reticulum tubular network biogenesis; also, it is located at the tip of neurons in the axonal growth cone, it directs the growth and development of the axons which transmit nerve impulses [14][15][16][17][18]. Mutations in the ATL1 gene are more common with early-onset HSP patients.…”