2. Academic Validation
  3. A Biallelic Mutation in the Homologous Recombination Repair Gene SPIDR Is Associated With Human Gonadal Dysgenesis

A Biallelic Mutation in the Homologous Recombination Repair Gene SPIDR Is Associated With Human Gonadal Dysgenesis

  • J Clin Endocrinol Metab. 2017 Feb 1;102(2):681-688. doi: 10.1210/jc.2016-2714.
Pola Smirin-Yosef 1 2,  Nehama Zuckerman-Levin 3 4,  Shay Tzur 5 6,  Yaron Granot 5,  Lior Cohen 7 8 9,  Juliane Sachsenweger 10,  Guntram Borck 11,  Irina Lagovsky 2 9,  Mali Salmon-Divon 1,  Lisa Wiesmüller 10,  Lina Basel-Vanagaite 2 7 8 9
Affiliations

Affiliations

  • 1 Genomic Bioinformatics Laboratory, Department of Molecular Biology, Ariel University, Ariel 40700, Israel.
  • 2 Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva 4941492, Israel.
  • 3 Clalit Health Services, Sharon-Shomron District 42505, Israel.
  • 4 Pediatric Diabetes and Obesity Clinic, Rambam Medical Center, Bruce Rappaport Faculty of Medicine-Technion, Haifa 3200003, Israel.
  • 5 Laboratory of Molecular Medicine, Rambam Health Care Campus, Haifa 3109601, Israel.
  • 6 Genomic Research Department, Emedgene Technologies, Tel-Aviv 6789126, Israel.
  • 7 Raphael Recanati Genetics Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva 4941492, Israel.
  • 8 Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petah Tikva 49202, Israel.
  • 9 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
  • 10 Department of Obstetrics and Gynecology, Ulm University, Ulm 89075, Germany.
  • 11 Institute of Human Genetics, ULM University, Ulm 89081, Germany; and.
PMID: 27967308 DOI: 10.1210/jc.2016-2714
Abstract

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 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.

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 γH2AX-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.

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