A Missense Mutation in SLC33A1, which Encodes the Acetyl-CoA Transporter, Causes Autosomal-Dominant Spastic Paraplegia (SPG42)

Abstract

Hereditary spastic paraplegias (HSPs), characterized by progressive and bilateral spasticity of the legs, are usually caused by developmental failure or degeneration of motor axons in the corticospinal tract. There are considerable interfamilial and intrafamilial variations in age at onset and severity of spasticity. Genetic studies also showed that there are dozens of genetic loci, on multiple chromosomes, that are responsible for HSPs. Through linkage study of a pedigree of HSP with autosomal-dominant inheritance, we mapped the causative gene to 3q24-q26. Screening of candidate genes revealed that the HSP is caused by a missense mutation in the gene for acetyl-CoA transporter (SLC33A1). It is predicted that the missense mutation, causing the change of the highly conserved serine to arginine at the codon 113 (p. S113R), disrupts the second transmembrane domain in the transporter and reverses the orientation of all of the descending domains. Knockdown of Slc33a1 in zebrafish caused a curve-shaped tail and defective axon outgrowth from the spinal cord. Although the wild-type human SLC33A1 was able to rescue the phenotype caused by Slc33a1 knockdown in zebrafish, the mutant SLC33A1 (p.S113R) was not, suggesting that S113R mutation renders SLC33A1 nonfunctional and one that wild-type allele is not sufficient for sustaining the outgrowth and maintenance of long motor axons in human heterozygotes. Thus, our study illustrated a critical role of acetyl-CoA transporter in motor-neuron development and function.

A total of 220 patients with autosomal dominant spastic paraplegia do not display mutations in the SLC33A1 gene (SPG42)

“…10 In addition, SLC33A1 has an unusually high content of Alu sequences (38.1% compared with the B10% genomic average 21 ). In other genes, such high values are associated with an increased susceptibility to genomic deletions (ie, MSH2).…”

“…11 It is hypothesized that the modification of gangliosides and glycoproteins by acetylation probably has a critical role in the outgrowth and maintenance of axons of motor neurons. 10 The frequency of SPG42 and its associated phenotypes is not known, as no further families with SLC33A1 mutations have been described so far. 10 The purpose of this study was to determine the frequency of SPG42 by screening 220 European (German, French, Norwegian) ADHSP patients for conventional and gene dosage mutations.…”

“…10 The frequency of SPG42 and its associated phenotypes is not known, as no further families with SLC33A1 mutations have been described so far. 10 The purpose of this study was to determine the frequency of SPG42 by screening 220 European (German, French, Norwegian) ADHSP patients for conventional and gene dosage mutations.…”

“…On the basis of the detection of a serine-toarginine substitution at codon113 in this family, the authors reported SLC33A1 (MIM# 603690) to be the responsible gene. 10 The protein product of SLC33A1 is an acetyl-CoA transporter, which serves as a substrate of acetyltransferases that modify the sialyl residues of gangliosides and glycoproteins. 11 It is hypothesized that the modification of gangliosides and glycoproteins by acetylation probably has a critical role in the outgrowth and maintenance of axons of motor neurons.…”

Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

“…Children with homozygous mutations in AT‐1/SLC33A1 display congenital defects, severe developmental delay, and premature death (Chiplunkar et al, 2016; Huppke et al, 2012). Patients with heterozygous mutations appear normal at birth but then develop a complicated autosomal dominant form of spastic paraplegia (Lin et al, 2008). Finally, chromosomal duplications of the 3q25.31 locus, which harbors AT‐1/SLC33A1 , have been reported in patients with autism spectrum disorder (ASD), intellectual disability, propensity to seizures, and facial dysmorphism (SFARI database; see also Swisshelm et al 2014.…”