Spastic paraplegia type 4: A novel SPAST splice site donor mutation and expansion of the phenotype variability
Graphical abstract
Introduction
Hereditary spastic paraplegia (HSP) includes a heterogeneous group of neurodegenerative disorders characterized by slowly progressive spasticity and weakness of the lower limbs. To date, > 67 spastic paraplegia genes (SPGs) have been identified and their cellular functions or localisation include mitochondria, axonal transport, lipid metabolism, DNA repair and nucleotide metabolism, myelination, autophagy, neuronal development, synapse, endosomes, ERAD pathway, protein folding, ER membrane modelling, etc. [1], [2]. SPG4/SPAST, encoding spastin, is a member of the ATPases Associated with diverse cellular Activities (AAA) family and has biological roles in microtubule dynamics and membrane trafficking. Mutations in SPAST are the most frequent molecular aetiology for familial autosomal dominant HSP. Most of SPG4 patients show a pure form, but phenotypic variations are also reported [3]. A loss-of-function mechanism or haploinsufficiency has been reported as molecular pathogenesis in SPG4. It has also been reported that decreased levels of spastin would lead to insufficient microtubule severing and less dynamic microtubules [4]. We performed a genetic screening and investigated a new mutation in seven SPG4 patients from two families.
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Participants and clinical assessments
The study was performed according to a protocol reviewed and approved by the Institutional Review Boards (IRBs) of the Tokushima University Hospital, as well as by the Ethics Committee of the Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Santa Lucia, Rome, Italy. All participants provided written informed consent for all aspects of the study, according to the Declaration of Helsinki. A cohort of patients with spastic paraplegia recruited in Italy (n = 126) and Japan (n = 58) was
Identification of a novel SPAST splice site donor variant
Exome capture sequencing achieved a mean read depth of > 50 × across all coding exons of SPG genes, which was sufficiently covered to pass our thresholds for calling SNPs and indels. A novel SPAST intronic variation was found in three affected members in Japanese family (TKSM-201501) and four affected members in Italian family (RM-1251), and absent in unaffected members (Fig. 1A and B). The variant is located at the third position at 5′-splice-site of intron 6, c.1004 + 3A > C, which is highly
Discussion
We report a novel SPG4/SPAST splice site donor variant, c.1004 + 3A > C, in two families, one from Japan and the other from Italy. The SPG4/SPAST intronic variant was co-segregated with the disease phenotype in both families; genotyping of unaffected members and our control datasets (618 control chromosomes) did not detect it. Moreover, the variant is not registered in any public database as rare normal variant or mutation in SPG4/SPAST. This indicates that the variant is associated with the
Disclosure statement
The authors declare no conflicts of interest.
Acknowledgements
We are grateful to patients and their family members and healthy donors for their participation in this study. The authors thank Ms. Akemi Takahashi for her technical support. We also thank Michela Renna, MA, for the language advice, as well as the Support Center for Advanced Medical Sciences, Tokushima University School of Medicine, for the use of their facilities to prepare the manuscript. We are extremely grateful to the Genetic Bank of the Laboratorio di Neurogenetica, CERC-IRCCS Santa Lucia
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