title: A Biallelic Mutation in the Homologous Recombination Repair Gene SPIDR Is Associated With Human Gonadal Dysgenesis.
abstract: Primary ovarian insufficiency (POI) is caused by ovarian follicle depletion or follicle dysfunction, characterized by amenorrhea with elevated gonadotropin levels. The disorder presents as absence of normal progression of puberty.
  
  
  
  To elucidate the cause of ovarian dysfunction in a family with POI.
  
  
  
  We performed whole-exome sequencing in 2 affected individuals. To evaluate whether DNA double-strand break (DSB) repair activities are altered in biallelic mutation carriers, we applied an enhanced green fluorescent protein-based assay for the detection of specific DSB repair pathways in blood-derived cells.
  
  
  
  Diagnoses were made at the Pediatric Endocrine Clinic, Clalit Health Services, Sharon-Shomron District, Israel. Genetic counseling and sample collection were performed at the Pediatric Genetics Unit, Schneider Children's Medical Center Israel, Petah Tikva, Israel.
  
  
  
  Two sisters born to consanguineous parents of Israeli Muslim Arab ancestry presented with a lack of normal progression of puberty, high gonadotropin levels, and hypoplastic or absent ovaries on ultrasound. Blood samples for DNA extraction were obtained from all family members.
  
  
  
  Exome analysis to elucidate the cause of POI in 2 affected sisters.
  
  
  
  Analysis revealed a stop-gain homozygous mutation in the SPIDR gene (KIAA0146) c.839G>A, p.W280*. This mutation altered SPIDR activity in homologous recombination, resulting in the accumulation of 53BP1-labeled DSBs postionizing radiation and γH2AX-labeled damage during unperturbed growth.
  
  
  
  SPIDR is important for ovarian function in humans. A biallelic mutation in this gene may be associated with ovarian dysgenesis in cases of autosomal recessive inheritance.
authors.affiliation: Genomic Bioinformatics Laboratory, Department of Molecular Biology, Ariel University, Ariel 40700, Israel.|Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva 4941492, Israel.
authors.forename: Pola
authors.initials: P
authors.lastname: Smirin-Yosef
authors.affiliation: Clalit Health Services, Sharon-Shomron District 42505, Israel.|Pediatric Diabetes and Obesity Clinic, Rambam Medical Center, Bruce Rappaport Faculty of Medicine-Technion, Haifa 3200003, Israel.
authors.forename: Nehama
authors.initials: N
authors.lastname: Zuckerman-Levin
authors.affiliation: Laboratory of Molecular Medicine, Rambam Health Care Campus, Haifa 3109601, Israel.|Genomic Research Department, Emedgene Technologies, Tel-Aviv 6789126, Israel.
authors.forename: Shay
authors.initials: S
authors.lastname: Tzur
authors.affiliation: Laboratory of Molecular Medicine, Rambam Health Care Campus, Haifa 3109601, Israel.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Granot
authors.affiliation: Raphael Recanati Genetics Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva 4941492, Israel.|Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petah Tikva 49202, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
authors.forename: Lior
authors.initials: L
authors.lastname: Cohen
authors.affiliation: Department of Obstetrics and Gynecology, Ulm University, Ulm 89075, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Sachsenweger
authors.affiliation: Institute of Human Genetics, ULM University, Ulm 89081, Germany; and.
authors.forename: Guntram
authors.initials: G
authors.lastname: Borck
authors.affiliation: Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva 4941492, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
authors.forename: Irina
authors.initials: I
authors.lastname: Lagovsky
authors.affiliation: Genomic Bioinformatics Laboratory, Department of Molecular Biology, Ariel University, Ariel 40700, Israel.
authors.forename: Mali
authors.initials: M
authors.lastname: Salmon-Divon
authors.affiliation: Department of Obstetrics and Gynecology, Ulm University, Ulm 89075, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Wiesmüller
authors.affiliation: Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva 4941492, Israel.|Raphael Recanati Genetics Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva 4941492, Israel.|Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petah Tikva 49202, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
authors.forename: Lina
authors.initials: L
authors.lastname: Basel-Vanagaite
mesh_terms: D000293:Adolescent; D000483:Alleles; D002648:Child; D003241:Consanguinity; D004268:DNA-Binding Proteins; D059472:Exome; D005260:Female; D006059:Gonadal Dysgenesis / Q000000981:diagnostic imaging* / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007557:Israel; D009154:Mutation; D009687:Nuclear Proteins; D010375:Pedigree; D016649:Primary Ovarian Insufficiency / Q000000981:diagnostic imaging* / Q000235:genetics*; D011506:Proteins / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011506:Proteins; C582833:SPIDR protein, human