title: Disruption of POF1B binding to nonmuscle actin filaments is associated with premature ovarian failure.
abstract: Premature ovarian failure (POF) is characterized by elevated gonadotropins and amenorrhea in women aged <40 years. In a Lebanese family with five sisters who received the diagnosis of POF, we established linkage to the long arm of the X chromosome (between Xq21.1 and Xq21.3.3), using whole-genome SNP typing and homozygosity-by-descent mapping. By sequencing one candidate gene within that region, POF1B, we identified a point mutation localized in exon 10. This substitution of a nucleotide (G-->A), at position 1123, results in an arginine-->glutamine mutation of the protein sequence at position 329 (mutation R329Q). All the affected family members were homozygous for the mutation, whereas the unaffected members were heterozygous. Because POF1B shares high homology with the tail portion of the human myosin, we assessed the ability of both wild-type and mutant POF1B proteins to bind nonmuscle actin filaments in vitro. We found that the capacity of the mutant protein to bind nonmuscle actin filaments was diminished fourfold compared with the wild type, suggesting a function of POF1B in germ-cell division. Our study suggests that a homozygous point mutation in POF1B influences the pathogenesis of POF by altering POF1B binding to nonmuscle actin filaments.
authors.affiliation: Department of Human Genetics, University of California at Los Angeles, 90095, USA.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Lacombe
authors.forename: Hane
authors.initials: H
authors.lastname: Lee
authors.forename: Laila
authors.initials: L
authors.lastname: Zahed
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Choucair
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Muller
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
authors.forename: Wael
authors.initials: W
authors.lastname: Salameh
authors.forename: Eric
authors.initials: E
authors.lastname: Vilain
mesh_terms: D000199:Actins / Q000378:metabolism*; D001483:Base Sequence; D041321:Chromosomes, Human, X; D017931:DNA Primers; D005091:Exons; D005260:Female; D008040:Genetic Linkage; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008840:Microfilament Proteins; D010375:Pedigree; D017354:Point Mutation; D016649:Primary Ovarian Insufficiency / Q000235:genetics*; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*
chemical_list: D000199:Actins; D017931:DNA Primers; D008840:Microfilament Proteins; C500687:POF1B protein, human; D011506:Proteins