Reader in Endocrine Genetics
Lou Metherell graduated from the University of Manchester with BSc (Hons) Biology 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 Endocrinology department at Queen Mary University of London in 1998, headed by Professor Adrian Clark. Her research is focussed on the genetics of endocrine disorders. In 2008, she was awarded a New Investigator Research Grant from the Medical Research Council. She was appointed a Reader in Endocrine Genetics in 2012.
Summary of Research
Familial Glucocorticoid Deficiency (FGD)
Through genetic 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 (see cartoons) that promote adrenocortical development and glucocorticoid production. Recent advances in understanding the pathogenesis of these life-threatening conditions include: 1) identifying that a form of FGD in the Irish Traveller community is attributable to mutation of MCM4, which encodes a component of the MCM2-7 complex essential for normal DNA replication and genome stability in all eukaryotes; 2) appreciation that the adrenal gland is a highly dynamic organ that undergoes constant remodelling to maintain homeostasis (in collaboration with Peter King), in part through recruitment of differentiated steroidogenic cells into the zona fasciculata or zona glomerulosa from stem/progenitor cell populations and antioxidant defence mechanisms; and 3) establishing that mutations in four genes (e.g. NNT, TXNRD2, PRDX3, GPX1) cause a FGD phenotype indistinguishable from that attributable to ACTH receptor pathway defects, and that the products of these four genes are intimately involved in maintaining mitochondrial redox homeostasis.
Growth hormone insensitivity (GHI)
Our group has a long history in growth disorder research and now acts as an international diagnostic sequencing service for GHI cases, led by Helen Storr. 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 publist publications click here
Högler W, Martin DD, Crabtree N, Nightingale P, Tomlinson J, Metherell L, Rosenfeld R, Hwa V, Rose S, Walker J, Shaw N, Barrett T, Frystyk J. IGFALS gene dosage effects on serum IGF-I and glucose metabolism, body composition, bone growth in length and width, and the pharmacokinetics of recombinant human IGF-I administration. J Clin Endocrinol Metab. 2014 Jan 13:jc20133718. [Epub ahead of print]
Prasad R, Metherell LA, Clark AJ, Storr HL. Deficiency of ALADIN impairs redox homeostasis in human adrenal cells and inhibits steroidogenesis. Endocrinology. (2013) 154(9):3209-18
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.