Primary gonadal failure is characterized by a lack of spontaneous pubertal development, primary amenorrhea or early menopause in females, and underdeveloped testis and azoospermia in males. Its genetic causes remain mostly unknown.<\/p>\n
Variants of the minichromosome maintenance complex component 8 gene (MCM8) are significantly associated with early menopause. Mice lacking MCM8 are sterile. We sought to elucidate the genetic etiology of gonadal failure in two consanguineous families: family 1’s index case presented with primary amenorrhea and her brother had azoospermia; family 2’s five affected females had primary amenorrhea.<\/p>\n
Using whole-exome sequencing, we identified two novel homozygous mutations in MCM8\u2014splice (c.1954-1G>A) and frameshift (c.1469-1470insTA)\u2014that segregated with the disease and were absent in 100 ethnically matched controls. The splice mutation (family 1) led to three different aberrant transcripts and a significant decrease in total MCM8 message. The frameshift mutation (family 2) predicted a premature stop codon. DNA-repair capabilities showed significantly increased chromosomal breakage.<\/p>\n
Our findings indicate that MCM8 is crucial for gonadal development and maintenance and suggest its relevance in the larger context of reproductive lifespan in humans. (By Dr. Yardena Tenenbaum-Rakover, http:\/\/jmg.bmj.com\/content\/52\/6\/391<\/a> )<\/p>\n
![\"Figure](\"https:\/\/stg-blogs.bmj.com\/jmg\/files\/2015\/08\/Figure-1-300x286.jpg\")
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