The prolactin receptor gene (PRLR) is linked and associated with the risk of polycystic ovarian syndrome.

The prolactin receptor gene (PRLR) may contribute to polycystic ovarian syndrome (PCOS) since it plays important roles in physiological ovarian functions. PRLR-knockout mice have irregular cycles and subfertility and variants in or around the PRLR gene were associated in humans with female testosterone levels and recurrent miscarriage. We tested 40 variants in the PRLR gene in 212 Italian families phenotyped by type 2 diabetes (T2D) and PCOS and found two intronic PRLR-variants (rs13436213 and rs1604428) significantly linked to and/or associated with the risk of PCOS. This is the first study to report PRLR as a novel risk gene in PCOS. Functional studies are needed to confirm these results.

Novel corticotropin-releasing hormone receptor genes (CRHR1 and CRHR2) linkage to and association with polycystic ovary syndrome.

BACKGROUND: Women with polycystic ovarian syndrome (PCOS) have increased hypothalamic-pituitary-adrenal (HPA) axis activation, pro-inflammatory mediators, and psychological distress in response to stressors. In women with PCOS, the corticotropin-releasing hormone (CRH) induces an exaggerated HPA response, possibly mediated by one of the CRH receptors (CRHR1 or CRHR2). Both CRHR1 and CRHR2 are implicated in insulin secretion, and variants in CRHR1 and CRHR2 genes may predispose to the mental-metabolic risk for PCOS. METHODS: We phenotyped 212 Italian families with type 2 diabetes (T2D) for PCOS following the Rotterdam diagnostic criteria. We analyzed within CRHR1 and CRHR2 genes, respectively, 36 and 18 microarray-variants for parametric linkage to and/or linkage disequilibrium (LD) with PCOS under the recessive with complete penetrance (R1) and dominant with complete penetrance (D1) models. Subsequentially, we ran a secondary analysis under the models dominant with incomplete penetrance (D2) and recessive with incomplete penetrance (R2). RESULTS: We detected 22 variants in CRHR1 and 1 variant in CRHR2 significantly (p < 0.05) linked to or in LD with PCOS across different inheritance models. CONCLUSIONS: This is the first study to report CRHR1 and CRHR2 as novel risk genes in PCOS. In silico analysis predicted that the detected CRHR1 and CRHR2 risk variants promote negative chromatin activation of their related genes in the ovaries, potentially affecting the female cycle and ovulation. However, CRHR1- and CRHR2-risk variants might also lead to hypercortisolism and confer mental-metabolic pleiotropic effects. Functional studies are needed to confirm the pathogenicity of genes and related variants.

Linkage and association of variants in the dopamine receptor 2 gene (DRD2) with polycystic ovary syndrome.

Polycystic ovarian syndrome (PCOS) is a disorder with a foundation of neuroendocrine dysfunction, characterized by increased gonadotropin-releasing hormone (GnRH) pulsatility, which is antagonized by dopamine. The dopamine receptor 2 (DRD2), encoded by the DRD2 gene, has been shown to mediate dopamine's inhibition of GnRH neuron excitability through pre- and post-synaptic interactions in murine models. Further, DRD2 is known to mediate prolactin (PRL) inhibition by dopamine, and high blood level of PRL have been found in more than one third of women with PCOS. We recently identified PRL as a gene contributing to PCOS risk and reported DRD2 conferring risk for type 2 diabetes and depression, which can both coexist with PCOS. Given DRD2 mediating dopamine's action on neuroendocrine profiles and association with metabolic-mental states related to PCOS, polymorphisms in DRD2 may predispose to development of PCOS. Therefore, we aimed to investigate whether DRD2 variants are in linkage to and/or linkage disequilibrium (i.e., linkage and association) with PCOS in Italian families. In 212 Italian families, we tested 22 variants within the DRD2 gene for linkage and linkage disequilibrium with PCOS. We identified five novel variants significantly linked to the risk of PCOS. This is the first study to identify DRD2 as a risk gene in PCOS, however, functional studies are needed to confirm these results.

Novel variants causing megalencephalic leukodystrophy in Sudanese families.

Mutations in MLC1 cause megalencephalic leukoencephalopathy with subcortical cysts (MLC), a rare form of leukodystrophy characterized by macrocephaly, epilepsy, spasticity, and slow mental deterioration. Genetic studies of MLC are lacking from many parts of the world, especially in Sub-Saharan Africa. Genomic DNA was extracted for 67 leukodystrophic patients from 43 Sudanese families. Mutations were screened using the NGS panel testing 139 leukodystrophies and leukoencephalopathies causing genes (NextSeq500 Illumina). Five homozygous MLC1 variants were discovered in seven patients from five distinct families, including three consanguineous families from the same region of Sudan. Three variants were missense (c.971 T > G, p.Ile324Ser; c.344 T > C, p.Phe115Ser; and c.881 C > T, p.Pro294Leu), one duplication (c.831_838dupATATCTGT, p.Ser280Tyrfs*8), and one synonymous/splicing-site mutation (c.762 C > T, p.Ser254). The segregation pattern was consistent with autosomal recessive inheritance. The clinical presentation and brain MRI of the seven affected patients were consistent with the diagnosis of MLC1. Due to the high frequency of distinct MLC1 mutations found in our leukodystrophic Sudanese families, we analyzed the coding sequence of MLC1 gene in 124 individuals from the Sudanese genome project in comparison with the 1000-genome project. We found that Sudan has the highest proportion of deleterious variants in MLC1 gene compared with other populations from the 1000-genome project.