A de novo SPAST mutation leading to somatic mosaicism is associated with a later age at onset in HSP

Centre hospitalier Agen, Agen, Aquitaine, France
Neurogenetics (Impact Factor: 2.88). 09/2007; 8(3):231-3. DOI: 10.1007/s10048-007-0090-4
Source: PubMed


SPG4/SPAST, the gene-encoding spastin, is responsible for the most frequent form of autosomal dominant hereditary spastic paraplegia (HSP). SPG4-HSP is a heterogeneous disorder characterized by both interfamilial and intrafamilial variation, especially regarding the severity and the age at onset. In this study, we investigated the origin of the mutation and the factors involved in intra-familial heterogeneity in a family with a SPG4 mutation. We demonstrated that the mutation occurred de novo and show evidence of somatic mosaicism in the grandfather, who was the only affected member of six siblings. His disease began at age 55, much later than in his daughter, who had onset at age 18, and his grandson, in whom onset was at age 5. These observations indicate that de novo mutations can occur in SPG4, and that somatic mosaicism might account for intra-familial variation in SPG4-linked HSP.

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    • "In Alzheimer's disease, a case with mosaicism from somatic mutation of presenilin-1 was described, with 14% mutant DNA in the cortex.23 Hereditary spastic paraplegia caused by mosaicism for a spastin mutation has been reported.24 Very recently, a novel form of neurodegeneration with brain iron accumulation has been found to be a result of mutations in WDR45, with a somatic origin in some cases.25 Mosaicism for triplet-repeat neurodegenerative disorders from somatic mutation of the expanded repeat has been described,26,27 including fragile X premutation syndrome, in which somatic instability in brain appears more pronounced than in blood,28 and c9orf72 in amyotrophic lateral sclerosis.29 "
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    ABSTRACT: Alpha-synuclein (SNCA) is crucial in the pathogenesis of Parkinson's disease (PD), yet mutations in the SNCA gene are rare. Evidence for somatic genetic variation in normal humans, also involving the brain, is increasing, but its role in disease is unknown. Somatic SNCA mutations, arising in early development and leading to mosaicism, could contribute to PD pathogenesis and yet be absent or undetectable in DNA derived from peripheral lymphocytes. Such mutations could underlie the widespread pathology in PD, with the precise clinical outcome dependent on their type and the timing and location of their occurrence. We recently reported a novel SNCA mutation (c.150T>G, p.H50Q) in PD brain-derived DNA. To determine if there was mosaicism for this, a PCR and cloning strategy was used to take advantage of a nearby heterozygous intronic polymorphism. No evidence of mosaicism was found. High-resolution melting curve analysis of SNCA coding exons, which was shown to be sensitive enough to detect low proportions of 2 known mutations, did not reveal any further mutations in DNA from 28 PD brain-derived samples. We outline the grounds that make the somatic SNCA mutation hypothesis consistent with genetic, embryological, and pathological data. Further studies of brain-derived DNA are warranted and should include DNA from multiple regions and methods for detecting other types of genomic variation. © 2013 Movement Disorder Society.
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    ABSTRACT: Hereditary spastic paraplegias (HSPs) are genetically heterogeneous mendelian disorders characterized by weakness and spasticity in the lower limbs associated with additional neurologic signs in "complex" or "complicated" forms. Major advances have been made during the past two decades in our understanding of their molecular bases. The mapping of 34 genes (17 of which have been identified) involved in this clinically diverse group of disorders has highlighted their great genetic heterogeneity. From the combined genetic and clinical information obtained, a new classification is now emerging that will help to better diagnose this condition, evaluate disease progression, guide follow-up, and permit genetic counselling. Evidence is now accumulating that at least part of the physiopathology results from abnormal intracellular trafficking, as well as from altered cell recognition and signaling, oligodendroglial dysfunction, mitochondrial defects, and impaired cholesterol and/or neurosteroid metabolism.
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