A de novo SPAST mutation leading to somatic mosaicism is associated with a later age at onset in HSP
ABSTRACT 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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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.Current Neurology and Neuroscience Reports 06/2008; 8(3):198-210. DOI:10.1007/s11910-008-0032-z · 3.67 Impact Factor
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ABSTRACT: Somatic mosaicism is well known in disorders where the manifestations are readily seen, e.g. the skin in neurofibromatosis I. In single gene disorders of higher frequency, especially X-linked ones, the frequency of combined germ-line and somatic mosaicism is increasingly being appreciated, e.g. Duchenne Muscular Dystrophy. Cell separation techniques; such as the fluorescence-activated cell sorter (FACS) also detect much somatic mosaicism among blood cells in disorders such as paroxysmal nocturnal hemoglobinuria. Depending on the disorder and the class of mutation, in genes for which there are sufficient numbers of patients studied, 6-20% of cases are due to somatic mutation. This update of my previous review is stimulated by the rapid application of new technologies for the study of DNA variation in disease. The results of these studies implicate somatic mutation in a greater variety of genetic diseases and a wider spectrum of tissues than have previously been shown, including heart and kidney. The classes of mutation have also expanded beyond base pair changes, insertions/deletion (indels), and short tandem repeat mutations to include copy number variants and transposon-mediated mutations. I also briefly discuss previously well-known mosaicism for chromosomal mutations. Genomic sequencing, performed on DNA from blood, shows many mutations which are conclusively somatic in origin. It is still too early to see if there is a different pattern of somatic mutation compared to germ-line mutation. Though the parameters to allow careful quantification are not yet available, it seems that the frequency of gene mutation in embryonic cells is not markedly different than that in the germ line.Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 10/2010; 705(2):96-106. DOI:10.1016/j.mrrev.2010.04.002 · 4.44 Impact Factor