title: A multi-exonic SPG4 duplication underlies sex-dependent penetrance of hereditary spastic paraplegia in a large Brazilian pedigree.
abstract: 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.
authors: Departamento de Genética e Biologia Evolutiva, Human Genome Research Center, Bioscience Institute, University of São Paulo, São Paulo, Brazil. mmitne@gmail.com
authors: Miguel
authors: M
authors: Mitne-Neto
authors: Fernando
authors: F
authors: Kok
authors: Christian
authors: C
authors: Beetz
authors: André
authors: A
authors: Pessoa
authors: Clarissa
authors: C
authors: Bueno
authors: Zodja
authors: Z
authors: Graciani
authors: Marcilia
authors: M
authors: Martyn
authors: Carlos B M
authors: CB
authors: Monteiro
authors: Guilherme
authors: G
authors: Mitne
authors: Paulo
authors: P
authors: Hubert
authors: Anders O H
authors: AO
authors: Nygren
authors: Marcos
authors: M
authors: Valadares
authors: Antonia M P
authors: AM
authors: Cerqueira
authors: Alessandra
authors: A
authors: Starling
authors: Thomas
authors: T
authors: Deufel
authors: Mayana
authors: M
authors: Zatz
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D001938:Brazil; D005091:Exons / Q000235:genetics*; D005260:Female; D020440:Gene Duplication; D006579:Heterozygote; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D019683:Penetrance; D012727:Sex Characteristics; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*; D000074181:Spastin
chemical_list: D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human