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The William Harvey Research Institute - Faculty of Medicine and Dentistry

REF Impact Statements and Gene Panels

Research in the Centre for Endocrinology under the leadership of Professor Louise Metherell has greatly improved diagnosis and understanding of Adrenal Insufficiency, characterising recessive gene mutations and developing a novel and cost-effective genetic screening panel, which is helping patients to receive swift, appropriate, effective treatment and genetic counselling for this life-threatening disorder.
Professor Helen Storr has led on the development of a genetic panel for diagnosing short stature. Short stature affects ~2% of UK children and is a common reason for referral (~50%) to paediatric endocrinology clinics. Approximately half of short children referred to specialty clinics have a treatable condition but most (80-90%) do not currently obtain a diagnosis. Queen Mary’s centre is recognised as an international referral centre for genetic testing of patients with undiagnosed growth failure. The short stature gene panel has reduced the diagnostic time and more than 60% of patients referred have obtained a specific genetic diagnosis which has led to targeted treatment and management plans.

Impact
Key Publications

Demonstration of how BRAF and, more generally MAPK signalling, contribute to pituitary development, a key advance stemming from genetic studies showing that mutations activating MAPK pathway components cause congenital hypopituitarism. (Dr Carles Gaston-Massuet, Nat Comm, 2021).
https://www.nature.com/articles/s41467-021-21712-4.pdf
Discovery of co-driver pathogenic somatic mutations in aldosterone-producing adenomas of women presenting with hypertension in the first trimester of pregnancy, the period of peak human Chorionic Gonadotropin (Professors Morris Brown & Helen Storr, Nat Gen, in press 2021).
Discovery of a novel genetic cause of delayed puberty in boys increases our understanding of the processes regulating the timely migration of neurons from the vomeronasal organ in the nose to the hypothalamus during embryonic life. (Professor Leo Dunkel and Dr Sasha Howard, JCI Insight, 2020).
https://insight.jci.org/articles/view/133434
Discovery that the neurohormone dopamine signals through a specific receptor-combination(s) in early-stage Huntington’s disease, identifying a novel therapeutic target (Dr P McCormick, eLife 2020).
https://elifesciences.org/articles/51093
Demonstrated that metformin reduces the adverse metabolic side-effects of glucocorticoids, which could potentially benefit as many as 3% of the adult UK population (Professor Márta Korbonits, Lancet Diabetes and Endocrinology 2020). https://www.thelancet.com/journals/landia/article/PIIS2213-8587(20)30021-8/fulltext. This paper was accompanied by an Editorial entitled Metformin: the white knight fighting corticosteroid side-effects. https://www.thelancet.com/journals/landia/article/PIIS2213-8587(20)30040-1/fulltext
Proof-of-principle that pro-active, clinical surveillance of asymptomatic people with AIP mutations, the most common cause of genetically-determined acromegaly and gigantism, has real clinical benefit: earlier intervention, reducing disease severity and complications. (Professor Márta Korbonits, JCEM 2020).
https://academic.oup.com/jcem/article/105/6/e2247/5717684
Recognition that one of the most common mouse sub-strain used in the research community has a mutation causing dilated cardiomyopathy. (Professor Louise Metherell, Life Sci Alliance, 2020).
https://www.life-science-alliance.org/content/3/4/e201900593
Discovery that contrary to expectations that the pseudokinase Tribbles 1 in arterial macrophages promotes uptake of atherogenic lipoproteins and that silencing this protein in this cell-type could be therapeutically targeted to reduce atherosclerosis (Professor Carol Shoulders, Sci Adv, 2019).
https://advances.sciencemag.org/content/5/10/eaax9183
Reader’s choice award 2019 for the most significant contribution to the field in 2018. Demonstration that recombinant human insulin growth factor improves height outcomes in children with short stature due a homozygous intronic pseudoexon growth hormone receptor mutation. (Professor Helen Storr, Eur J Endocrin, 2018).
https://eje.bioscientifica.com/view/journals/eje/178/5/EJE-18-0042.xml
Key mechanistic discoveries (i) the aryl hydrocarbon receptor interacting protein (AIP) contributes to adaptive immune responses via regulation of AKT signalling; and ii) expression of AIP in diffuse large B cell lymphomas correlates with disease severity and pathobiology via regulation of de-ubiquitinases. (Professor Márta Korbonits in collaboration with Dr Oliver Haworth, Cell Reports 2019).
https://www.cell.com/cell-reports/fulltext/S2211-1247(19)30469-3
Development of novel method for making steroidogenic cells from fibroblasts, blood- and urine-derived cells that could enable the study of adrenal disease in a personalized manner. Translation potential: opens up venues for developing precision therapies for adrenal insufficiency (Dr Leo Guasti, Cell Reports 2018).
https://www.cell.com/cell-reports/fulltext/S2211-1247(18)30003-2
Development of a conceptual model for studying feedback loops regulating the architecture of dermis, and thus of skin, the largest endocrine organ of the body. (Dr Emanuel Rognoni, Molecular Systems Biology 2018).
https://www.embopress.org/doi/full/10.15252/msb.20178174
Discovery MRAP2 in the hypothalamic paraventricular nucleus that regulates food intake and energy expenditure (Dr Li Chan, Molecular Metabolism 2018).
https://www.sciencedirect.com/science/article/pii/S2212877818307932?via%3Dihub
Identification of a heterozygous germline mutation in a β-cell–enriched transcription factor in a series of families that causes diabetes in some family members and insulinomatosis in others, with a strong gender specificity. The effect of the mutation on protein stability helps explain the gender-specific dichotomous phenotype (Professor Márta Korbonits, PNAS 2018).
https://www.pnas.org/content/115/5/1027.long
Discovery that pseudohypoxia associated with genetic causes of pheochromocytoma and paragangliomas (tumours of the adrenal gland & autonomic nervous system) disrupts primary cilia-mediated signalling pathways associated with tumorigenesis and cancer. (Professor Paul Chapple, Endocr Relat Cancer 2018).
https://erc.bioscientifica.com/view/journals/erc/26/1/ERC-18-0134.xml
Discovery of key molecular mechanism underlying the neurodegenerative disease ARSACS caused by loss of Sacsin: this large protein regulates intermediate filament cytoskeleton assembly and dynamics (Professor Paul Chapple, Hum Mol Gen 2017). https://academic.oup.com/hmg/article/26/16/3130/3848995
Discovery that the hypothalamic-derived hormone kisspeptin binds to specific receptors in the fetal adrenal gland, thereby regulating fetal adrenal steroidogenesis, and the integrity of the fetoplacental unit, particularly in the second trimester of pregnancy. (Professor Helen Storr, JCEM 2017).
https://academic.oup.com/jcem/article/102/9/3349/3882601
First description of a novel syndrome of adrenal insufficiency and steroid-resistant nephrotic syndrome and discovery of the genetic cause of this multi-organ disorder: impaired sphingolipid catabolism due to loss-of-function SGPL1 mutations (Dr Rathi Prasad, Professor Louise Metherell, JCI 2017).
https://www.jci.org/articles/view/90171
Identification of a genetic cause of delayed puberty highlights the contribution of a previously uncharacterised protein (IGSF10) in steering migration of gonadotropin-releasing hormone neurons during embryonic development (Dr Sasha Howard, Professor Leo Dunkel, EMBO Mol Med 2016).
https://www.embopress.org/doi/pdf/10.15252/emmm.201606250
Established that the repressor functions of Transcription factor 7-like 1 are required for the development of the hypothalmus-pituary axis and, that loss of this repression causes a rare form of congenital hypopituitarism (Dr Carles Gaston-Massuet, PNAS, 2016). https://www.pnas.org/content/113/5/E548.long.
Discovered novel role for a collagen XVIII isoform in adipose tissue accrual and metabolism. (Professor Carol Shoulders, PNAS, 2014). https://www.pnas.org/content/111/30/E3043.long