A biallelic mutation in the homologous recombination repair gene SPIDR is associated with human gonadal dysgenesis

Pola Smirin-Yosef, Nehama Zuckerman-Levin, Shay Tzur, Yaron Granot, Lior Cohen, Juliane Sachsenweger, Guntram Borck, Irina Lagovsky, Mali Salmon-Divon, Lisa Iesmüller, Lina Basel-Vanagaite

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


Context: 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. Objective: To elucidate the cause of ovarian dysfunction in a family with POI. Design: 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. Setting: 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. Patients and Intervention: Two sisters born to consanguineous parents of IsraeliMuslim Arab ancestry presented with a lack of normal progression of puberty, high gonadotropin levels, and hypoplastic or absent ovaries on ultrasound. Blood samples forDNAextractionwere obtained from all familymembers. Main Outcome Measure: Exome analysis to elucidate the cause of POI in 2 affected sisters. Results: 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 gH2AX-labeled damage during unperturbed growth. Conclusions: 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.

Original languageEnglish
Pages (from-to)681-688
Number of pages8
JournalJournal of Clinical Endocrinology and Metabolism
Issue number2
StatePublished - 1 Feb 2017
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical


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