A multi-exonic SPG4 duplication underlies sex-dependent penetrance of hereditary spastic paraplegia in a large Brazilian pedigree.
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.
Mitne-Neto
Miguel
M
Departamento de Genética e Biologia Evolutiva, Human Genome Research Center, Bioscience Institute, University of São Paulo, São Paulo, Brazil. mmitne@gmail.com
Kok
Fernando
F
Beetz
Christian
C
Pessoa
André
A
Bueno
Clarissa
C
Graciani
Zodja
Z
Martyn
Marcilia
M
Monteiro
Carlos B M
CB
Mitne
Guilherme
G
Hubert
Paulo
P
Nygren
Anders O H
AO
Valadares
Marcos
M
Cerqueira
Antonia M P
AM
Starling
Alessandra
A
Deufel
Thomas
T
Zatz
Mayana
M
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
D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human