Gene of the month: STK11

2021 ◽  
pp. jclinpath-2021-207906
Author(s):  
Roman E Zyla ◽  
Elan Hahn ◽  
Anjelica Hodgson
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Poor Response ◽  
Loss Of Function ◽  
Hamartomatous Polyps ◽  
Lung Cancers ◽  
Physiological Processes ◽  
Mucocutaneous Pigmentation ◽  
Liver Kinase B1 ◽  
Peutz Jeghers Syndrome ◽  
Amp Activated Protein Kinase

STK11 encodes for the protein liver kinase B1, a serine/threonine kinase which is involved in a number of physiological processes including regulation of cellular metabolism, cell polarity and the DNA damage response. It acts as a tumour suppressor via multiple mechanisms, most classically through AMP-activated protein kinase-mediated inhibition of the mammalian target of rapamycin signalling pathway. Germline loss-of-function mutations in STK11 give rise to Peutz-Jeghers syndrome, which is associated with hamartomatous polyps of the gastrointestinal tract, mucocutaneous pigmentation and a substantially increased lifetime risk of many cancers. In the sporadic setting, STK11 mutations are commonly seen in a subset of adenocarcinomas of the lung in addition to a number of other tumours occurring at various sites. Mutations in STK11 have been associated with worse prognoses across a range of malignancies and may be a predictor of poor response to immunotherapy in a subset of lung cancers, though further studies are needed before the presence of STK11 mutations can be implemented as a routine clinical biomarker.

scholarly journals Bladder hamartoma in Peutz-Jeghers syndrome: a rare case report

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Jai Kumar ◽  
Mohammad Irfaan Albeerdy ◽  
Nadeem Ahmed Shaikh ◽  
Abdul Hafeez Qureshi
Keyword(s):  
Urinary Bladder ◽  
Filling Defect ◽  
Hamartomatous Polyps ◽  
Case Presentation ◽  
Rare Case Report ◽  
Mucocutaneous Pigmentation ◽  
Dominant Disease ◽  
Peutz Jeghers Syndrome ◽  
Comprehensive Compilation

Abstract Background Peutz-Jeghers syndrome is an autosomal dominant disease characterized by mucocutaneous pigmentation and hamartomatous polyps in the gastrointestinal tract (GIT). There have also been cases of extra GIT polyps such as the renal pelvis, urinary bladder, lungs and nares. Bladder hamartoma is an extremely rare finding, with only 12 cases described in the literature up to now. The rarity of the condition necessitates a comprehensive compilation of managements up to now so as to provide a better tool for the treatment of such conditions in the future. Case presentation A twenty-year-old male, known to have Peutz-Jeghers syndrome, presented to us complaining of obstructive urinary symptoms. A urethrogram done showed a filling defect at the base of the urinary bladder. The mass was resected transurethrally, and histopathology revealed a hamartoma of the bladder. The patient has since remained tumor-free on follow-up. Conclusions Transurethral resection of the bladder mass proved to be an effective therapy in this patient with no recurrence on the patient’s follow-up till now. There is still, however, a dearth of knowledge regarding the management of bladder hamartomas owing to the extreme rarity of the case.

scholarly journals Recurrent Abdominal Pain in Peutz-Jeghers Syndrome: A Case Report

2019 ◽  
Vol 37 (3) ◽  
pp. 160-164
Author(s):  
Sayeeda Anwar ◽  
Nusrat Kamal ◽  
Rokeya Khanom ◽  
Subrota Kumar Roy ◽  
Farzana Kabir ◽  
...  
Keyword(s):  
Abdominal Pain ◽  
Autosomal Dominant ◽  
Recurrent Abdominal Pain ◽  
Hamartomatous Polyps ◽  
Recurrent Vomiting ◽  
Mucocutaneous Pigmentation ◽  
Peutz Jeghers Syndrome ◽  
Supportive Management ◽  
Black Pigmentation

Peutz-Jeghars Syndrome (PJS), also known as peri-orificial lentiginosis, is a condition of autosomal dominant inheritance. Here, mutation localized at (19p13.3) LKB1/ STK11. It is characterized by presence of mucocutaneous pigmentation and gastrointestinal (GI) hamartomatous polyps. This case of PJS, is a 7 year old girl who came with recurrent vomiting and abdominal pain for 1 year and weight loss for 8 months. She had multiple black pigmentation over lips and buccal mucosa. Endoscopy revealed multiple polyps in stomach and duodenum. Besides supportive management, polyps were removed by surgical intervention. Biopsy of these polyps showed hamartomatous type. Post operative period was uneventful. She recovered well. So far there was no recurrence of pain. She is on regular follow up. J Bangladesh Coll Phys Surg 2019; 37(3): 160-164

scholarly journals LKB1: cancer, polarity, metabolism, and now fertility

2008 ◽  
Vol 416 (1) ◽  
pp. e1-e3 ◽  
Author(s):  
Reuben J. Shaw
Keyword(s):  
Translational Regulation ◽  
Cell Metabolism ◽  
Familial Cancer ◽  
Control Cell ◽  
Serine Threonine Kinase ◽  
Lung Cancers ◽  
C Terminus ◽  
Biochemical Journal ◽  
Peutz Jeghers Syndrome ◽  
Amp Activated Protein Kinase

The LKB1 serine/threonine kinase is a tumour suppressor responsible for the inherited familial cancer disorder Peutz-Jeghers syndrome and is inactivated in a large percentage of human lung cancers. LKB1 acts a master kinase, directly phosphorylating and activating a family of 14 AMPK (AMP-activated protein kinase)-related kinases which control cell metabolism, cell growth and cell polarity. In this issue of the Biochemical Journal, Hardie and colleagues discover an alternative splice form of LKB1 that alters the C-terminus of the protein containing a few known sites of post-translational regulation. Although widely expressed, the short isoform (LKB1s) is the sole splice isoform expressed in testes, and its expression peaks at the time of spermatid maturation. Male mice lacking the LKB1s isoform have dramatic defects in spermatozoa, resulting in sterility.

scholarly journals Insulin resistance and sarcopenia: mechanistic links between common co-morbidities

2016 ◽  
Vol 229 (2) ◽  
pp. R67-R81 ◽  
Author(s):  
Mark E Cleasby ◽  
Pauline M Jamieson ◽  
Philip J Atherton
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Mammalian Target Of Rapamycin ◽  
Later Life ◽  
The Elderly ◽  
Clinical Syndrome ◽  
Physiological Processes ◽  
Age Related ◽  
Increased Risk ◽  
Amp Activated Protein Kinase

Insulin resistance (IR) in skeletal muscle is a key defect mediating the link between obesity and type 2 diabetes, a disease that typically affects people in later life. Sarcopenia (age-related loss of muscle mass and quality) is a risk factor for a number of frailty-related conditions that occur in the elderly. In addition, a syndrome of ‘sarcopenic obesity’ (SO) is now increasingly recognised, which is common in older people and is applied to individuals that simultaneously show obesity, IR and sarcopenia. Such individuals are at an increased risk of adverse health events compared with those who are obese or sarcopenic alone. However, there are no licenced treatments for sarcopenia or SO, the syndrome is poorly defined clinically and the mechanisms that might explain a common aetiology are not yet well characterised. In this review, we detail the nature and extent of the clinical syndrome, highlight some of the key physiological processes that are dysregulated and discuss some candidate molecular pathways that could be implicated in both metabolic and anabolic defects in skeletal muscle, with an eye towards future therapeutic options. In particular, the potential roles of Akt/mammalian target of rapamycin signalling, AMP-activated protein kinase, myostatin, urocortins and vitamin D are discussed.

scholarly journals Obstructing Hamartomatous Polyp in Peutz-Jeghers Syndrome

2013 ◽  
Vol 2013 ◽  
pp. 1-3
Author(s):  
Brian S. Bentley ◽  
Hassan M. Hal
Keyword(s):  
Weight Loss ◽  
Abdominal Pain ◽  
Soft Tissue ◽  
Oral Mucosa ◽  
Physical Exam ◽  
Hamartomatous Polyp ◽  
Hamartomatous Polyps ◽  
Mucocutaneous Pigmentation ◽  
Soft Tissue Masses ◽  
Peutz Jeghers Syndrome

A 53-year-old male presented with complaints of abdominal pain and weight loss. On physical exam he was noted to have mucocutaneous pigmentation around his lips and oral mucosa. Radiologic and endoscopic investigations demonstrated an obstructing mass in the second portion of the duodenum along with additional smaller soft tissue masses throughout the bowel. Histology of biopsied specimens revealed architectural disorganization without dysplasia, suggestive of Peutz-Jeghers hamartomatous polyps.

LKB1 mutations in mucinous bronchioloalveolar carcinoma occurring in Peutz-Jeghers syndrome patients

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 11047-11047
Author(s):  
A. Osoegawa ◽  
Y. Takeda ◽  
T. Kometani ◽  
K. Ondo ◽  
S. Fukuyama ◽  
...  
Keyword(s):  
Direct Sequencing ◽  
Bronchioloalveolar Carcinoma ◽  
Lung Carcinogenesis ◽  
Gene Encoding ◽  
Independent Sequence ◽  
Ethical Approval ◽  
Mucocutaneous Pigmentation ◽  
Liver Kinase B1 ◽  
Peutz Jeghers Syndrome ◽  
Tissue Specimens

11047 Background: Mutations in the gene encoding Liver Kinase B1, LKB1, are common in patients with Peutz-Jeghers syndrome (PJS), which is characterized by mucocutaneous pigmentation, intestinal polyps and a high incidence of cancers at variable sites (colorectal, gynecological, breast, pancreas, and lung). Although tumors occurring in PJS patients are known to contain mucin-rich conmponents, mucinous bronchioloalveolar carcinomas (mBACs) arising from the PJS background have only rarely been reported. Here we report two mBAC patients with PJS. We further explored the LKB1 gene in these two patients and, in addition, eight sporadic mBAC patients. Methods: Frozen tissue specimens were collected from ten mBAC patients who underwent surgery in our department from 2002 to 2008, and high molecular weight genomic DNA was extracted from them and stocked in the bio-bank. Written informed consent was obtained from each patient, and ethical approval was obtained from the IRB. The nucleotide sequence of LKB1 (EX01–09) was determined by genomic PCR-direct sequencing. Loss of heterozygosity (LOH) was analyzed by high resolution fluorescent microsatellite analysis (HRFMA) using two microsatellite markers that encompass the LKB1 locus, D19S886 and D19S565. Results: Among 11 tumors derived from the 10 patients, 9 distinct LKB1 mutations were found in 7 tumors (4 G:C to A:T transitions; 3 G:C to C:G transversions; 2 single nucleotide insetion/deletion). All of three tumors obtained from the two PJS patients harbored a same sequence alteration. Although LOH was not observed in these tumors, independent sequence alterations were found in two of the three tumors, which may suggest biallelic inactivation of LKB1 in tumors occurred in the PJS patients. Conclusions: The relatively high frequency of LKB1 mutation in mBAC patients may suggest its implication in lung carcinogenesis, at least in mBAC, and its potential as a therapeutic target. [Table: see text] No significant financial relationships to disclose.

scholarly journals Peutz-Jeghars’ syndrome, a rare genetic disorder: A case report

2020 ◽  
Vol 3 (7) ◽  
Author(s):  
Fabia Hannan Mone ◽  
Kuntal Roy ◽  
Gazi Zahirul Hasan, ◽  
Kaushik Roy ◽  
Qazi Sazib Ahamed, ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Genetic Disorder ◽  
Hamartomatous Polyps ◽  
Gastrointestinal Malignancy ◽  
Increased Risk ◽  
Hamartomatous Polyposis Syndromes ◽  
Mucocutaneous Pigmentation ◽  
Dominant Disease ◽  
Polyposis Syndromes ◽  
Peutz Jeghers Syndrome

Abstract: Hamartomatous polyposis syndromes or Peutz-Jeghers syndrome (PJS) is a hereditary autosomal dominant disease characterized by benign hamartomatous polyps and mucocutaneous pigmentation in the digestive tract. It occurs mostly in the small intestine during first decade of life but frequently in the colon and stomach. Only a few cases have been reported in the duodenum1. Polyposis syndromes are common cause of adult intussusceptions, with polyps acting as lead points. Adult intussusceptions are rare and is almost always associated with that lead point2. Although hamartomatous polyps are not pre-malignant, there is an increased risk of gastrointestinal and non-gastrointestinal malignancy, commonly involving the small bowel. Most patients of PJS presents with acute abdomen and diagnosed as intussusceptions, commonly entero-enteric type but colo-colic intussusceptions are rare in Peutz-Jeghers syndrome3. To the best of our knowledge, synchronous colo-colic intussusception association in Peutz-Jeghers syndrome has not been previously reported.

Giant Solitary Gastric Peutz-Jeghers Polyp Mimicking a Malignant Gastric Tumor: the Largest Described in Literature

2014 ◽  
Vol 23 (3) ◽  
pp. 321-324 ◽  
Author(s):  
Sorinel Lunca ◽  
Vlad Porumb ◽  
Natalia Velenciuc ◽  
Dan Ferariu ◽  
Gabriel Dimofte
Keyword(s):  
Upper Gastrointestinal Bleeding ◽  
Rare Event ◽  
Gastric Tumor ◽  
Node Metastasis ◽  
Mucocutaneous Pigmentation ◽  
History Of ◽  
Peutz Jeghers Syndrome ◽  
Upper Gastrointestinal ◽  
Gastric Malignancy ◽  
Polypoid Tumor

A solitary Peutz-Jeghers polyp is defined as a unique polyp occurring without associated mucocutaneous pigmentation or a family history of Peutz-Jeghers syndrome. Gastric solitary localization is a rare event, with only eight reported cases to date. We report herein the case of a 43-year old woman who presented with upper gastrointestinal bleeding, severe anemia, weight loss and asthenia. Endoscopy revealed a giant polypoid tumor with signs of neoplastic invasion of the cardia, with pathological aspect suggesting a Peutz-Jeghers hamartomatous polyp. Computed tomography suggested a malignant gastric tumor and a total gastrectomy was performed. The pathological specimen showed a giant 150/70/50 mm polypoid tumor and immunochemistry established the final diagnostic of a Peutz-Jegers type polyp. This is the largest solitary Peutz-Jeghers gastric polyp reported until now, and the second one mimicking a gastric malignancy with lymph node metastasis.

scholarly journals The Link between VAPB Loss of Function and Amyotrophic Lateral Sclerosis

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1865
Author(s):  
Nica Borgese ◽  
Nicola Iacomino ◽  
Sara Francesca Colombo ◽  
Francesca Navone
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Adaptor Proteins ◽  
Loss Of Function ◽  
Membrane Contact Sites ◽  
Physiological Processes ◽  
Main Driver ◽  
Single Allele ◽  
Induced Pluripotent ◽  
Lateral Sclerosis

The VAP proteins are integral adaptor proteins of the endoplasmic reticulum (ER) membrane that recruit a myriad of interacting partners to the ER surface. Through these interactions, the VAPs mediate a large number of processes, notably the generation of membrane contact sites between the ER and essentially all other cellular membranes. In 2004, it was discovered that a mutation (p.P56S) in the VAPB paralogue causes a rare form of dominantly inherited familial amyotrophic lateral sclerosis (ALS8). The mutant protein is aggregation-prone, non-functional and unstable, and its expression from a single allele appears to be insufficient to support toxic gain-of-function effects within motor neurons. Instead, loss-of-function of the single wild-type allele is required for pathological effects, and VAPB haploinsufficiency may be the main driver of the disease. In this article, we review the studies on the effects of VAPB deficit in cellular and animal models. Several basic cell physiological processes are affected by downregulation or complete depletion of VAPB, impinging on phosphoinositide homeostasis, Ca2+ signalling, ion transport, neurite extension, and ER stress. In the future, the distinction between the roles of the two VAP paralogues (A and B), as well as studies on motor neurons generated from induced pluripotent stem cells (iPSC) of ALS8 patients will further elucidate the pathogenic basis of p.P56S familial ALS, as well as of other more common forms of the disease.

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