A multi-exonic SPG4 duplication underlies sex-dependent penetrance of hereditary spastic paraplegia in a large brazilian pedigree
| Autor: | Alessandra Starling, Fernando Kok, Mayana Zatz, Guilherme Mitne, Marcilia Martyn, A Cerqueira, M. Valadares, Zodja Graciani, Carlos Bandeira de Mello Monteiro, Miguel Mitne-Neto, Thomas Deufel, André Pessoa, Christian Beetz, Paulo Hubert, Clarissa Bueno, Anders O H Nygren |
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| Rok vydání: | 2007 |
| Předmět: |
Adult
Male Heterozygote Spastin Adolescent Hereditary spastic paraplegia Pedigree chart Locus (genetics) Penetrance Kaplan-Meier Estimate Biology Gene Duplication Gene duplication Genetics medicine Humans Muscular dystrophy Gene Genetics (clinical) Adenosine Triphosphatases Sex Characteristics Spastic Paraplegia Hereditary Infant Exons Middle Aged medicine.disease GENÉTICA MÉDICA Pedigree Mutation Female Brazil |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| Popis: | SPG4 mutations are the most frequent cause of autosomal-dominant hereditary spastic paraplegia (HSP). SPG4 HSP is characterized by large inter- and intrafamilial variability in age at onset (AAO) and disease severity. The broad spectrum of SPG4 mutations has recently been further extended by the finding of large genomic deletions in SPG4-linked pedigrees negative for 'small' mutations. We had previously reported a very large pedigree, linked to the SPG4 locus with many affected members, which showed gender difference in clinical manifestation. Screening for copy number aberrations revealed the first case of a multi-exonic duplication (exon10_12dup) in the SPG4 gene. The mutation leads to a premature stop codon, suggesting that the protein product is not functional. The analysis of 30 individuals who carry the mutation showed that males have on average an earlier AAO and are more severely affected. The present family suggests that this HSP pathogenesis may be modulated by factors related to individual background and gender as observed for other autosomal dominant conditions, such as facio-scapulohumeral muscular dystrophy or amyloidosis. Understanding why some individuals, particularly women, are 'partially protected' from the effects of this and other pathogenic mutations is of utmost importance. |
| Databáze: | OpenAIRE |
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