Compound heterozygosity in the SPG4 gene causes hereditary spastic paraplegia

Clinical Genetics
D V K PantakaniA U Mannan

Abstract

The SPG4 gene is frequently mutated in autosomal dominant form of hereditary spastic paraplegia (HSP). We report that the compound heterozygous sequence variants S44L, a known polymorphism, and c.1687G>A, a novel mutation in SPG4 cause a severe form of HSP in a patient. The family members carrying solely c.1687G>A mutation are asymptomatic for HSP. The reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed that the c.1687G>A mutation is a splice site mutation and causes skipping of the exon 15 of spastin. Furthermore, quantification of RT-PCR products by sequencing and quantification of allele-specific expression by pyrosequencing assay revealed that c.1687G>A is a leaky or hypomorphic splice site mutation. At the protein level, c.1687G>A mutation in SPG4 leads to E563K substitution. In ex vivo study, about 10% of cells expressing E563K mutant spastin showed filamentous expression pattern, suggesting a hypomorphic effect at the protein level. Collectively, our results suggest that S44L in association with c.1687G>A (E563K) drops the functional level of spastin below a threshold limit sufficient to manifest HSP.

References

Mar 4, 2000·Human Molecular Genetics·N FonknechtenJ Hazan
Oct 4, 2000·Journal of Medical Genetics·J C LindseyK M Bushby
Apr 20, 2001·American Journal of Human Genetics·I K SvensonD A Marchuk
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Aug 20, 2003·Archives of Neurology·John K Fink
Jul 13, 2004·Neurogenetics·Ingrid K SvensonDouglas A Marchuk
Jul 13, 2006·Neurology·C J McDermottUNKNOWN UK and Irish HSP Consortium

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Citations

Jun 11, 2008·Current Neurology and Neuroscience Reports·Giovanni StevaninAlexis Brice
May 25, 2010·European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies·S KlimpeA U Mannan
Jul 26, 2015·Journal of the Neurological Sciences·Hyunwoong ParkMoon-Woo Seong
Aug 20, 2010·Clinical Genetics·D S McCorquodaleS Züchner
Jul 29, 2010·Journal of Cellular Physiology·Julia C FuerstDominikus Bönsch

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