Oestrogen excess phenotype associated with loss of heterozygosity of the <em>STK11</em> gene in the testis of two boys with Peutz Jeghers Syndrome — ASN Events
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Oestrogen excess phenotype associated with loss of heterozygosity of the STK11 gene in the testis of two boys with Peutz Jeghers Syndrome (#115)

Seungmin Ham 1 2 , Sarah J Meachem 1 3 , Catherine S Choong 4 5 , Adrian K Charles 6 , Gareth S Baynam 5 7 , Timothy W Jones 4 5 , Nirukshi U Samarajeewa 1 8 , Evan R Simpson 1 9 , Kristy A Brown 1 8
  1. Metabolism and Cancer Laboratory, Prince Henry’s Institute, Clayton, VIC, Australia
  2. Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
  3. Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia
  4. Paediatric Endocrinology, Genetic Services of Western Australia, Perth, WA, Australia
  5. School of Paediatrics and Child Health, The University of Western Australia, Perth, WA, Australia
  6. Pathology, Genetic Services of Western Australia, Perth, WA, Australia
  7. Princess Margaret Hospital for Children, Perth, WA, Australia
  8. Physiology, Monash University, Clayton, VIC, Australia
  9. Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia

Background:Peutz Jeghers syndrome (PJS) is an autosomal dominant disorder characterised by the association of gastrointestinal harmatomatous polyps and mucocutaneous pigmentation which is due to mutations in the STK11 gene that encodes the LKB1 protein. PJS males may have oestrogen excess manifesting as gynaecomastia and an advanced bone age. We and others have previously described an increase in testicular aromatase expression in PJS patients. However, the underlying mechanism has not yet been explored. The aim of this study was to characterise the role of LKB1 in regulating the expression of aromatase in the testes of two boys with PJS via signaling pathways involving pAMPK, CRTC1, CRTC2 and CRTC3.

Methods:We studied testicular biopsies from two boys with STK11 mutations; a 13-year-old boy and an unrelated 4-year-old boy with prepubertal gynaecomastia and advanced bone age.

Results:Loss of heterozygosity of STK11 in Sertoli cells of abnormal cords of PJS testis samples, measured by the absence of LKB1 immunofluorescent staining, was associated with loss of p21 expression and decreased phosphorylation of AMPK, known downstream targets of LKB1, as well as the increased expression of aromatase.  The cytoplasmic retention of the potent stimulator of aromatase CRTC3, which arises as a consequence of phosphorylation by AMPK, was decreased in cells where aromatase was detected.

Conclusions:Loss of heterozygosity of the STK11 gene leads to an increase in aromatase expression associated with loss of CRTC3 cytoplasmic retention, thereby providing a mechanism whereby PJS is associated with oestrogen excess.