Morbid Obesity And Spermatogenic Failure

A number sign (#) is used with this entry because of evidence that morbid obesity and spermatogenic failure (MOSPGF) is caused by homozygous mutation in the CEP19 gene (615586) on chromosome 3q29. One such family has been reported.

Clinical Features

Shalata et al. (2013) studied a large multigenerational Arab family in which 14 members had a BMI greater than 40. Obese family members all fulfilled criteria consistent with metabolic syndrome, including hypertension with systolic blood pressure greater than 140 mm Hg, fatty liver disease by ultrasound, and insulin resistance. Five affected family members had early coronary artery disease with myocardial infarction before 45 years of age, and 3 affected family members also had type II diabetes mellitus. Lipid profiles, although abnormal for a number of affected individuals, did not differ significantly from lean family members. Three of the affected individuals had intellectual disability, and all 6 affected males had decreased sperm counts: 4 were oligospermic and 2 were azoospermic.

Mapping

By positional cloning in a large multigenerational Arab family with morbid obesity and spermatogenic failure, Shalata et al. (2013) localized the disease gene to a 5.5-Mb region between markers D3S2418 and D3S3550 on the telomeric end of chromosome 3q29 (lod score of 9.7 at theta = 0). Heterozygosity and haplotype analysis narrowed the critical region to a 1.6-Mb interval between D3S2306 and D3S3550.

Molecular Genetics

In a large multigenerational Arab family with morbid obesity and spermatogenic failure mapping to chromosome 3q29, Shalata et al. (2013) analyzed 23 genes within the critical region and identified homozygosity for a nonsense mutation in the CEP19 gene (615586.0001) that segregated with obesity in the family and was not found in 620 controls, including 200 ethnically matched unaffected individuals, or in the dbSNP database (build 137).

Animal Model

Shalata et al. (2013) generated Cep19 -/- mice which, although they appeared normal at birth, grew significantly larger than their wildtype littermates in both length and mass. They became morbidly obese, with approximately twice the weight of controls, and were also hyperphagic, glucose intolerant, insulin resistant, and infertile. In Cep19 -/- testis, both spermatogenic cells and seminiferous tubules showed marked degeneration, and sperm had an abnormal crooked appearance and diminished motility.