Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Ovulatory response to treatment of polycystic ovary syndrome is associated with a polymorphism in the STK11 gene. Legro RS et al. CONTEXT: Clomiphene and insulin sensitizers such as metformin are used to induce ovulation in polycystic ovary syndrome (PCOS), but the ovulatory response is variable, and the causes of this variation are poorly understood. OBJECTIVE: Our objective was to identify predictive genetic polymorphisms and other determinants of ovulatory response. DESIGN: This was a substudy of a multicenter randomized clinical trial. SETTING: This study was performed at academic medical centers and their affiliates. PARTICIPANTS: A total of 312 women with PCOS were included in the study. MAIN OUTCOME MEASURES: Historical, biometric, biochemical, and genetic parameters were performed. RESULTS: We found that the C allele of a single nucleotide polymorphism in the STK11 gene (expressed in liver; also known as LKB1) was associated with a significantly decreased chance of ovulation in PCOS women treated with metformin. In an analysis of ovulation per cycle, the adjusted odds ratio (OR) comparing the C/C genotype to the G/G genotype was 0.30 [95% confidence interval (CI) 0.14, 0.66], and the OR for the C/G genotype vs. the G/G genotype was also 0.30 (95% CI 0.14, 0.66). In an analysis of metformin-treated subjects, we found that the percentage of women who ovulated increased with the number of G alleles present: 48% (10 of 21) of C/C women, 67% (32 of 48) of C/G women, and 79% (15 of 19) of G/G women ovulated. We also found that increased frequency of ovulation was associated with lower body mass index (BMI) [adjusted OR of 2.36 (95% CI 1.65, 3.36) and 2.05 (95% CI 1.46, 2.88), respectively, for comparisons of BMI less than 30 vs. BMI equal to or more than 35, BMI 30-34 vs. BMI equal to or more than 35, in the analysis of ovulation per cycle], a lower free androgen index (FAI) [adjusted OR of 1.59 (95% CI 1.17, 2.18) for FAI<10 vs. FAI>or=10], and a shorter duration of attempting conception [adjusted OR of 1.63 (95% CI 1.20, 2.21) for<1.5 vs.>or=1.5 yr]. CONCLUSIONS: We have demonstrated that a polymorphism in STK11, a kinase gene expressed in liver and implicated in metformin action, is associated with ovulatory response to treatment with metformin alone in a prospective randomized trial. The interaction with the effects of changes in modifiable factors (e.g. BMI or FAI) requires further study.

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Polycystic ovary syndrome (PCOS) with melanocytic mucosal macules: the role of STK11 gene polymorphisms in PCOS and Peutz-Jeghers syndrome. Smith KJ et al. (2015) Polycystic ovary syndrome (PCOS) is a complex genetic disorder that is the most common endocrinopathy that affects women. We report two individuals with PCOS with a genetic polymorphism in serine threonine kinase 11 (STK11). Both these individuals developed mucosal pigmentation suggesting Peutz-Jeghers syndrome (PJS), which is associated with mutations in STK11. Both individuals showed some improvement in their metabolic and endocrine dysregulation with therapies commonly used for PCOS. However, they continued to show progression of mucosa pigmentation. This is the first report of clinical overlap in individuals with PCOS and PJS, even though some individuals with PCOS show a polymorphism in STK11, which is the gene mutated in PJS. The importance of this clinical association is not clear but may be significant because of the association of STK11 dysregulation and the development of internal tumors.//////////////////

Species: human
Mutation name:
type: naturally occurring
fertility: fertile
Comment: Allele loss and mutation screen at the Peutz-Jeghers (LKB1) locus (19p13.3) in sporadic ovarian tumours. Wang ZJ et al. (1999) Germline mutations in the LKB1 (STK11) gene (chromosome sub-band 19p13.3) cause characteristic hamartomas and pigmentation to develop in patients with Peutz-Jeghers syndrome. Peutz-Jeghers syndrome carries an overall risk of cancer that may be up to 20 times that of the general population and Peutz-Jeghers patients are at increased risk of benign and malignant ovarian tumours, particularly granulosa cell tumours. Loss of heterozygosity (allele loss, LOH) has been reported in about 50% of ovarian cancers on 19p13.3. LKB1 is therefore a candidate tumour suppressor gene for sporadic ovarian tumours. We found allele loss at the marker D19S886 (19p13.3) in 12 of 49 (24%) sporadic ovarian adenocarcinomas. Using SSCP analysis, we screened ten ovarian cancers with LOH, 35 other ovarian cancers and 12 granulosa cell tumours of the ovary for somatic mutations in LKB1. No variants were detected in any of the adenocarcinomas. Two mutations were detected in one of the granulosa cell tumours: a mis-sense mutation affecting the putative 'start' codon (ATG --> ACG, M1T); and a silent change in exon 7 (CTT --> CTA, leucine). Like BRCA1 and BRCA2, therefore, it appears that LKB1 mutations can cause ovarian tumours when present in the germline, but occur rarely in the soma. The allele loss on 19p13.3 in ovarian cancers almost certainly targets a different gene from LKB1.//////////////////

Species: mouse
Mutation name:
type: null mutation
fertility: embryonic lethal
Comment: Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation. Zeqiraj E et al. (2009) The LKB1 tumor suppressor is a protein kinase that controls the activity of adenosine monophosphate-activated protein kinase (AMPK). LKB1 activity is regulated by the pseudokinase STRADalpha and the scaffolding protein MO25alpha through an unknown, phosphorylation-independent, mechanism. We describe the structure of the core heterotrimeric LKB1-STRADalpha-MO25alpha complex, revealing an unusual allosteric mechanism of LKB1 activation. STRADalpha adopts a closed conformation typical of active protein kinases and binds LKB1 as a pseudosubstrate. STRADalpha and MO25alpha promote the active conformation of LKB1, which is stabilized by MO25alpha interacting with the LKB1 activation loop. This previously undescribed mechanism of kinase activation may be relevant to understanding the evolution of other pseudokinases. The structure also reveals how mutations found in Peutz-Jeghers syndrome and in various sporadic cancers impair LKB1 function.//////////////////

Species: mouse
Mutation name:
type: null mutation
fertility: subfertile
Comment: LKB1 acts as a critical gatekeeper of ovarian primordial follicle pool. Jiang ZZ et al. (2016) Liver Kinase b1 (LKB1/STK11)is a tumor suppressor responsible for the Peutz-Jeghers syndrome, an autosomal-dominant, cancer-prone disorder in which patients develop neoplasms in several organs, including the oviduct, ovary, and cervix. Besides, the C allele of a SNP in the Lkb1 gene impedes the likelihood of ovulation in polycystic ovary syndrome (PCOS) in women treated with metformin, a known LKB1-AMPK activator. It is very likely that LKB1 plays roles in female fertility. To identify the physiological functions of LKB1 in the mouse ovary, we selectively disrupted LKB1 in oocytes by the Cre-LoxP conditional knockout system and found that Lkb1fl/fl; Gdf9-Cre mice were severely subfertile with significantly enlarged ovaries compared to Lkb1fl/fl mice. Interestingly, without Lkb1 expression in oocytes from the primordial follicle stage, the entire primordial follicle pool was activated but failed to mature and ovulate, subsequently causing premature ovarian failure (POF). Further investigation demonstrated that elevated mTOR signaling regulated by an AKT-independent LKB1-AMPK pathway was responsible for the excessive follicle activation and growth. Our findings reveal the role of LKB1 as an indispensable gatekeeper for the primordial follicle pool, offer new functional understanding for the tumor suppressor genes in reproductive organs, and might also provide valuable information for understanding POF and infertility.//////////////////