title: Propensity for paternal inheritance of de novo mutations in Alexander disease.
abstract: De novo dominant mutations in the GFAP gene have recently been associated with nearly all cases of Alexander disease, a rare but devastating neurological disorder. These heterozygous mutations must occur very early in development and be present in nearly all cells in order to be detected by the sequencing methods used. To investigate whether the mutations may have arisen in the parental germ lines, we determined the parental chromosome bearing the mutations for 28 independent Alexander disease cases. These cases included 17 different missense mutations and one insertion mutation. To enable assignment of the chromosomal origin of the mutations, six new single nucleotide polymorphisms in the GFAP gene were identified, bringing the known total to 26. In 24 of the 28 cases analyzed, the paternal chromosome carried the GFAP mutation (P < 0.001), suggesting that they predominantly arose in the parental germ line, with most occurring during spermatogenesis. No effect of paternal age was observed. There has been considerable debate about the magnitude of the male to female germ line mutation rate; our ratio of 6:1 is consistent with indirect estimates based on the rate of evolution of the sex chromosome relative to the autosomic chromosomes.
authors.affiliation: Department of Neurobiology and Civitan International Research Center 529, University of Alabama at Birmingham, 1530 3rd Avenue South, Birmingham, AL 35294-0021, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.forename: Anne B
authors.initials: AB
authors.lastname: Johnson
authors.forename: Gajja S
authors.initials: GS
authors.lastname: Salomons
authors.forename: Marjo S
authors.initials: MS
authors.lastname: van der Knaap
authors.forename: Diana
authors.initials: D
authors.lastname: Rodriguez
authors.forename: Odile
authors.initials: O
authors.lastname: Boespflug-Tanguy
authors.forename: J Rafael
authors.initials: JR
authors.lastname: Gorospe
authors.forename: James E
authors.initials: JE
authors.lastname: Goldman
authors.forename: Albee
authors.initials: A
authors.lastname: Messing
authors.forename: Michael
authors.initials: M
authors.lastname: Brenner
mesh_terms: D000328:Adult; D038261:Alexander Disease / Q000235:genetics*; D002648:Child; D004252:DNA Mutational Analysis; D005192:Family Health; D005220:Fathers; D005787:Gene Frequency; D005838:Genotype; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics*; D006801:Humans; D040582:Inheritance Patterns; D008423:Maternal Age; D009154:Mutation; D010331:Paternal Age; D020641:Polymorphism, Single Nucleotide
chemical_list: D005904:Glial Fibrillary Acidic Protein