Missense mutation of SPAST protein (I344K) results in loss of ATPase activity and prolonged the half-life, implicated in autosomal dominant hereditary spastic paraplegia.
These transgenic 'AD-HSP' flies therefore provide a powerful and tractable model to enhance our understanding of the cellular and behavioral consequences of human spastin mutations and test hypotheses directly relevant to the human disease.
We advocate that all spastin mutation negative AD-HSP kindreds should be screened for pathogenic atlastin mutations regardless of age of onset or phenotypic complexity.
The percentage of involved Chinese families with autosomal dominant hereditary spastic paraplegia with an SPG4 mutation is 18% (4/22), lower than the estimated 40% linked to this locus.
We performed mutation screening by direct sequencing of all 14 exons and flanking sequences of the SPG3A gene in affected individuals from 12 unrelated English families, all with an early onset uncomplicated ADHSP in whom spastin mutations had previously been excluded.
A total of eight loci for autosomal dominant hereditary spastic paraplegia (ADHSP) has been mapped to chromosome 14q, 2p, 15q, 8q, 10q, 12q, 19q, 2q, respectively, among which the SPG4 gene on chromosome 2p21-22 encoding spastin, an ATPase of the AAA family, accounts for 40-50% of all ADHSP families and is expressed in both adult and fetal tissues.
Laboratory analysis showed that the disorder was not caused by mutations in genes that cause SCA-1, SCA-2, SCA-3, SCA-6, SCA-7, SCA-8, and SCA-12; not linked to other known loci for autosomal dominant ataxia (SCA-4, SCA-5, SCA-10, SCA-11, SCA-13, SCA-14, and SCA-16); and not linked to known loci for autosomal dominant hereditary spastic paraplegia (HSP) (SPG-3, SPG-4, SPG-6, SPG-8, SPG-9, SPG-10, SPG-12, and SPG-13) or autosomal recessive HSP SPG-7.
Inheritance of HSP is commonly autosomal dominant, spastin was identified as the defective gene in chromosome 2p-linked autosomal dominant hereditary spastic paraplegia (AD-HSP).
Autosomal dominant hereditary spastic paraplegia 4 linked to chromosome 2p (SPG4) is the most common form of autosomal dominant hereditary spastic paraplegia.
Among these loci, the SPG4 locus on chromosome 2p21--p22 has been shown to account for approximately 40% of all autosomal dominant hereditary spastic paraplegia (ADHSP) families.Very recently, Hazan et al. identified the SPG4 gene encoding a new member of the AAA (ATPases associated with diverse cellular activities) protein family, named spastin.