Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability
Saleh AlAsiri, … , Michael A. Trakselis, Aleksandar Rajkovic
Saleh AlAsiri, … , Michael A. Trakselis, Aleksandar Rajkovic
Published December 1, 2014
Citation Information: J Clin Invest. 2015;125(1):258-262. https://doi.org/10.1172/JCI78473.
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Brief Report Genetics

Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability

Abstract

Premature ovarian failure (POF) is a genetically and phenotypically heterogeneous disorder that includes individuals with manifestations ranging from primary amenorrhea to loss of menstrual function prior to age 40. POF presents as hypergonadotropic hypogonadism and can be part of a syndrome or occur in isolation. Here, we studied 3 sisters with primary amenorrhea, hypothyroidism, and hypergonadotropic hypogonadism. The sisters were born to parents who are first cousins. SNP analysis and whole-exome sequencing revealed the presence of a pathogenic variant of the minichromosome maintenance 8 gene (MCM8, c.446C>G; p.P149R) located within a region of homozygosity that was present in the affected daughters but not in their unaffected sisters. Because MCM8 participates in homologous recombination and dsDNA break repair, we tested fibroblasts from the affected sisters for hypersensitivity to chromosomal breaks. Compared with fibroblasts from unaffected daughters, chromosomal break repair was deficient in fibroblasts from the affected individuals, likely due to inhibited recruitment of MCM8 p.P149R to sites of DNA damage. Our study identifies an autosomal recessive disorder caused by an MCM8 mutation that manifests with endocrine dysfunction and genomic instability.

Authors

Saleh AlAsiri, Sulman Basit, Michelle A. Wood-Trageser, Svetlana A. Yatsenko, Elizabeth P. Jeffries, Urvashi Surti, Deborah M. Ketterer, Sibtain Afzal, Khushnooda Ramzan, Muhammad Faiyaz-Ul Haque, Huaiyang Jiang, Michael A. Trakselis, Aleksandar Rajkovic

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Figure 1

Pedigree of a family with 3 daughters afflicted by premature ovarian failure and homozygous for the MCM8 c.446C>G variant.

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Pedigree of a family with 3 daughters afflicted by premature ovarian fai...
(A) Family members are designated by Arabic numerals. Horizontal lines between individuals represent marriage. Double horizontal lines indicate consanguinity in a marriage. Vertical lines represent lineage. Below each individual, the individual’s current age (if known) and MCM8 genotype are provided. (B) Sanger sequencing was used to validate genotypes, and representative chromatograms are shown. Individuals who are heterozygous for the c.446C>G MCM8 variant show overlapping C and G peaks (middle graph). Individuals homozygous for the c.446C>G MCM8 variant have a single G peak (bottom graph). (C) MCM8 is encoded on chromosome 20: 5,931,298-5,975,831 (NCBI37/hg19), and the c.446C>G variant in exon 5 is shown (red arrow). Full boxes represent exons (blue denotes coding sequences; green denotes noncoding sequences), and introns are indicated by lines. MCM8 consists of an N-terminal DNA-binding domain and a AAA+ core domain. The c.446C>G substitution caused a change in the amino acid sequence p.P149R within the predicted DNA-binding domain (red arrow). All domains are color coded with the homology model (Supplemental Figure 3).