Professor Lou Metherell
Professor of Endocrine Genetics
Email: email@example.comTelephone: +44(0) 20 7882 2148
Lou Metherell obtained a BSc in Biology from the University of Manchester BSc in 1985. During her undergraduate studies she developed an interest in genetics which led her to undertake a postgraduate diploma in Human Genetics at the University of Aberdeen. After a brief period in industry she returned to science and was awarded her PhD from the University of Greenwich in 1999. She joined the Centre for Endocrinology at WHRI in 1998, where her research has focused on the genetics of endocrine disease, particularly disorders of adrenal insufficiency. In 2008, she was awarded a New Investigator Research Grant from the Medical Research Council. She was appointed Reader in 2012 and Professor of Endocrine Genetics in 2017.
Dr Jack Williams
Dr Avinaash Vickram Maharaj
Ms Dominika Grzesik (with Professor Shoulders)
Familial Glucocorticoid Deficiency (FGD)
Through linkage mapping and next-generation sequencing of our cohort of FGD patients, our group has established that diseases of ACTH-resistance are genetically heterogeneous, involving mutations in a diverse range of genes that promote adrenocortical development and glucocorticoid production (see cartoons). Our most recent advances in understanding the pathogenesis of these life-threatening conditions include: 1) identifying syndromic forms of primary adrenal insufficiency caused by mutations in a) MCM4, encoding a component of the DNA replication machinery and b) SGPL1, encoding a degradative enzyme of sphingolipid metabolism; 2) demonstrating that partial loss-of-function mutations in STAR and CYP11A1 cause attenuated disease and 3) establishing that mutations in four redox genes (e.g. NNT, TXNRD2, PRDX3, GPX1) produce a glucocorticoid deficiency phenotype indistinguishable from that resulting from ACTH-resistance receptor pathway defects, for example, loss of MC2R and MRAP activity.
Figure 1. Gene defects recognised in our cohort of patients with primary adrenal insufficiency
Figure 2. Schematic of the ACTH receptor pathway and the transduceosome that transports cholesterol across the mitochondrial membrane
Figure 3. Redox homeostatic genes in the mitochondria (in red) that cause adrenal insufficiency
Figure 4. Partial loss of function mutations in CYP11A1 found in attenuated adrenal insufficiency
Growth hormone insensitivity (GHI)
The Centre for Endocrinology has a long history in researching growth disorders and now acts as an international diagnostic sequencing service for GHI cases, led by Helen Storr. Together we have uncovered causal mutations in many components of the GH-IGF1 signalling pathway, including a novel mechanism of pseudoexon activation in a case of atypical GHI.
For a full list of publications click here
- Ruiz-Babot G, Balyura M, Hadjidemetriou I, Ajodha SJ, Taylor DR, Ghataore L, Taylor NF, Schubert U, Ziegler CG, Storr HL, Druce MR, Gevers EF, Drake WM, Srirangalingam U, Conway GS, King PJ, Metherell LA, Bornstein SR, Guasti L. Modeling Congenital Adrenal Hyperplasia and Testing Interventions for Adrenal Insufficiency Using Donor-Specific Reprogrammed Cells. Cell Rep. (2018) 22(5):1236-1249.
- Meimaridou E, Goldsworthy M, Chortis V, Fragouli E, Foster PA, Arlt W, Cox R, Metherell LA. RNAseq reveals NNT is a key regulator of adrenal redox homeostasis and steroidogenesis in male mice. Journal of Endocrinology (2018) 236(1):13-28.
- Vairamani K, Merjaneh L, Casano-Sancho P, Sanli ME, David A, Metherell LA, Savage MO, Del Pozo JS, Backeljauw PF, Rosenfeld RG, Aisenberg J, Dauber A, Hwa V. Novel Dominant-Negative GH Receptor Mutations Expands the Spectrum of GHI and IGF-I Deficiency. J Endocr Soc. (2017) 1(4):345-358.
- Prasad R, Hadjidemetriou I, Maharaj A, Meimaridou E, Buonocore F, Saleem M, Hurcombe J, Bierzynska A, Barbagelata E, Bergadá I, Cassinelli H, Das U, Krone R, Hacihamdioglu B, Sari E, Yesilkaya E, Storr HL, Clemente M, Fernandez-Cancio M, Camats N, Ram N, Achermann JC, Van Veldhoven PP, Guasti L, Braslavsky D, Guran T, Metherell LA. Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome. J Clin Invest. (2017) 127(3):942-953
- Metherell LA, Guerra-Assunção JA, Sternberg MJ, David A. Three-Dimensional Model of Human Nicotinamide Nucleotide Transhydrogenase (NNT) and Sequence-Structure Analysis of its Disease-Causing Variations. Hum Mutat. 2016 Oct;37(10):1074-84.
- Howard S*, Guasti L*, Ruiz-Babot G, Mancini A, David A, Storr H, Metherell L, Sternberg M, Cabrera C, Warren H, Barnes M, Quinton R, de Roux N, Young J, Guiochon-Mantel A, Wehkalampi K, André V, Gothilf Y, Cariboni A, Dunkel L. IGSF10 deficiency dysregulates gonadotropin-releasing hormone neuronal migration and results in delayed puberty. EMBO Mol Med. (2016) 8(6):626-42.
- Prasad R, Chan LF, Hughes CR, Kaski JP, Kowalczyk JC, Savage MO, Peters CJ, Nathwani N, Clark AJ, Storr HL, Metherell LA. Thioredoxin reductase 2 (TXNRD2) mutation associated with familial glucocorticoid deficiency (FGD). J Clin Endocrinol Metab. (2014) 99(8):E1556-63.
- Meimaridou E, Hughes CR, Kowalczyk J, Guasti L, Chapple JP, King PJ, Chan LF, Clark AJ, Metherell LA. Familial glucocorticoid deficiency: New genes and mechanisms. Mol Cell Endocrinol. 2013 371(1-2): 195-200.
- Meimaridou E, Kowalczyk J, Guasti L, Hughes CR, et al., Chapple JP, King PJ, Clark AJL, Metherell LA. Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency. Nat Genet (2012) 44(7):740-2
- Hughes CR, Guasti L, Meimaridou E, Chuang CH, Schimenti JC, King PJ, Costigan C, Clark AJ, Metherell LA. MCM4 mutation causes adrenal failure, short stature, and natural killer cell deficiency in humans. J Clin Invest. (2012) 122(3):814-20.
- Turan S, Hughes C, Atay Z, Guran T, Haliloglu B, Clark AJ, Bereket A, Metherell LA. An Atypical Case of Familial Glucocorticoid Deficiency without Pigmentation Caused by Coexistent Homozygous Mutations in MC2R (T152K) and MC1R (R160W). J Clin Endocrinol Metab. (2012) 97(5):E771-4.
- Metherell LA, et al., Clark AJL. Non-classic lipoid congenital adrenal hyperplasia masquerading as familial glucocorticoid deficiency. J Clin Endocrinol Metab. (2009) 94(10):3865-71.
- Metherell LA, Chapple JP, Cooray S, David A, Becker C, et al., Nurnberg P, Huebner A, Cheetham ME, Clark AJ. Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2. Nat Genet. (2005) 37:166-70.
- Metherell LA, Akker SA, Munroe PB, Rose SJ, Savage MO, Chew SL & Clark AJL. (2001) Pseudoexon activation as a novel mechanism for disease resulting in atypical growth hormone insensitivity. American Journal of Human Genetics 69: 641 - 646.
Internal: Dr Helen Storr, Dr Li Chan, Dr Leo Guasti, Dr Peter King, Prof Paul Chapple, Prof Carol Shoulders.
External: Professor Angela Huebner (Technical University of Dresden); Professor Roger Cox (MRC Harwell, Oxford): Professor Xingen Lei (Cornell University), Professor Paul Van Veldhoven (KU Leuven, Belgium), Dr John Achermann (UCL, London), Dr Christa Fluck (University of Bern, Switzerland).