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Compound heterozygosity in the SPG4 gene causes hereditary spastic paraplegia
Author(s) -
Pantakani DVK,
Zechner U,
Arygriou L,
Pauli S,
Sauter SM,
Mannan AU
Publication year - 2008
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/j.1399-0004.2007.00953.x
Subject(s) - hereditary spastic paraplegia , compound heterozygosity , genetics , mutation , biology , exon , microbiology and biotechnology , mutant , splice site mutation , gene , loss of heterozygosity , allele , alternative splicing , phenotype
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.