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Genetics of Human Hypothalamic-Pituitary Development
My group is currently investigating the genetic basis of pituitary and forebrain development, particularly in relation to the aetiology of disorders of forebrain and hypothalamo-pituitary development and function. We have established the genetic basis of hypopituitarism in a significant number of patients presenting to the Paediatric Endocrinology clinics. We collaborate with many national and international clinical and non-clinical scientists with the aim of improving our understanding of the causes, diagnosis and treatment of these conditions. We have access to large cohorts of patients treated at GOSH and UCLH, and the molecular studies are underpinned by careful clinical phenotyping.
Main Funding: GOSHCC, MRF, Children with Cancer
Our current areas of interest include:
1) Genetic basis of hypothalamic-pituitary disorders
We have a long track record in discovering new genetic causes of human hypothalamic-pituitary disorders involving genes such as HESX1, PROP1, SOX3, LHX3/4, and more recently ARNT2 and EIF2S3. We have on-going interests in gene discovery, together with Genomics England and the 100k genomes project, as well as studying model systems of pituitary disease with a view to developing new treatment options.
2) Understanding the natural history of septo-optic dysplasia (SOD) and multiple pituitary hormone deficiency (MPHD)
We are undertaking long-term cohort follow up studies to better understand the natural progression of endocrine deficiencies and other associated non-endocrine, neurocognitive and behavioural abnormalities in children with SOD and MPHD, and to relate these to specific aspects of neuroimaging. We are developing new approaches to neuroimaging to define aspects of these conditions related to brain structure and function. Ultimately these studies will allow genotype-phenotype correlations which will equip us to better manage these highly complex patients through their life course.
3) Isolated hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS)
My group are interested in the molecular basis of gonadotropin synthesis and release in conditions such as IHH, KS and related syndromes such as CHARGE. We described the role of the key pluripotent stem cell factor SOX2 in hypothalamo-pituitary dysfunction and are involved in research to identify new genetic causes and mechanisms of related conditions.
4) Clinical studies in patients with isolated growth hormone insufficiency/deficiency (GHI/GHD)
We are currently undertaking a range of clinical studies to better understand and manage children with a range of disorders associated with growth hormone insufficiency/deficiency. In particular, we are focusing on the question of reversibility of GHI/GHD, with a view to further understanding the mechanisms underlying reversibility.
5) Hypothalamic Obesity
We are currently undertaking studies to understand the pathophysiological mechanisms underlying hypothalamic obesity, a condition that is prevalent in those patients with brain tumours as well as congenital disorders of hypothalamo-pituitary development such as Septo-Optic Dysplasia.
In addition to these specific areas of research, we have interests in a wide range of paediatric endocrine conditions such as thyroid disorders (THRA, IGSF1), growth disorders (STAT5B) and adrenal and reproductive dysfunction.
Key references
Gregory LC, Ferreira CB, Young-Baird SK, Williams HJ, Harakalova M, van Haaften G, Rahman SA, Gaston-Massuet C, Kelberman D, GOSgene, Qasim W, Camper SA, Dever TE, Shah P, Robinson ICAF, Dattani MT. Impaired EIF2S3 function associated with a novel phenotype of X-linked hypopituitarism with glucose dysregulation. EBioMedicine. 2019 Apr; 42:470-480. doi: 10.1016/j.ebiom.2019.03.013. Epub 2019 Mar 14. PMID: 30878599
Klammt J, Neumann D, Gevers EF, Andrew SF, Schwartz ID, Rockstroh D, Colombo R, Sanchez MA, Vokurkova D, Kowalczyk J, Metherell LA, Rosenfeld RG, Pfäffle R, Dattani MT, Dauber A, Hwa V. Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation. Nat Commun. 2018 May 29;9(1):2105. doi: 10.1038/s41467-018-04521-0. PMID: 29844444
Gaston-Massuet C, McCabe MJ, Scagliotti V, Young RM, Carreno G, Gregory LC, Jayakody SA, Pozzi S, Gualtieri A, Basu B, Koniordou M, Wu CI, Bancalari RE, Rahikkala E, Veijola R, Lopponen T, Graziola F, Turton J, Signore M, Mousavy Gharavy SN, Charolidi N, Sokol SY, Andoniadou CL, Wilson SW, Merrill BJ, Dattani MT, Martinez-Barbera JP. Transcription factor 7-like 1 is involved in hypothalamo-pituitary axis development in mice and humans. Proc Natl Acad Sci U S A. 2016 Feb 2; 113(5):E548-57. doi: 10.1073/pnas.1503346113. Epub 2016 Jan 13. PMID: 26764381
Webb EA, AlMutair A, Kelberman D, Bacchelli C, Chanudet E, Lescai F, Andoniadou CL, Banyan A, Alsawaid A, Alrifai MT, Alahmesh MA, Balwi M, Mousavy-Gharavy SN, Lukovic B, Burke D, McCabe MJ, Kasia T, Kleta R, Stupka E, Beales PL, Thompson DA, Chong WK, Alkuraya FS, Martinez-Barbera JP, Sowden JC, Dattani MT. ARNT2 mutation causes hypopituitarism, post-natal microcephaly, visual and renal anomalies. Brain. 2013 Oct;136(Pt 10):3096-105. doi: 10.1093/brain/awt218. Epub 2013 Sep 10.PMID: 24022475
Sun Y, Bak B, Schoenmakers N, van Trotsenburg AS, Oostdijk W, Voshol P, Cambridge E, White JK, le Tissier P, Gharavy SN, Martinez-Barbera JP, Stokvis-Brantsma WH, Vulsma T, Kempers MJ, Persani L, Campi I, Bonomi M, Beck-Peccoz P, Zhu H, Davis TM, Hokken-Koelega AC, Del Blanco DG, Rangasami JJ, Ruivenkamp CA, Laros JF, Kriek M, Kant SG, Bosch CA, Biermasz NR, Appelman-Dijkstra NM, Corssmit EP, Hovens GC, Pereira AM, den Dunnen JT, Wade MG, Breuning MH, Hennekam RC, Chatterjee K, Dattani MT, Wit JM, Bernard DJ. Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement. Nat Genet. 2012 Dec;44(12):1375-81. doi: 10.1038/ng.2453. Epub 2012 Nov 11. PMID: 23143598
Bochukova E, Schoenmakers N, Agostini M, Schoenmakers E, Rajanayagam O, Keogh JM, Henning E, Reinemund J, Gevers E, Sarri M, Downes K, Offiah A, Albanese A, Halsall D, Schwabe JW, Bain M, Lindley K, Muntoni F, Vargha-Khadem F, Dattani M, Farooqi IS, Gurnell M, Chatterjee K. A mutation in the thyroid hormone receptor alpha gene. N Engl J Med. 2012 Jan 19; 366(3):243-9. doi: 10.1056/NEJMoa1110296. Epub 2011 Dec 14. Erratum in: N Engl J Med. 2012 Oct 11;367(15):1474. Khadem, Faraneh Vargha [corrected to Vargha-Khadem, Faraneh]. PMID: 22168587
Kelberman D, Rizzoti K, Avilion A, Bitner-Glindzicz M, Cianfarani S, Collins J, Chong WK, Kirk JM, Achermann JC, Ross R, Carmignac D, Lovell-Badge R, Robinson IC, Dattani MT. Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans. J Clin Invest. 2006 Sep;116(9):2442-55. Epub 2006 Aug 24. PMID: 16932809
Dattani MT, Martinez-Barbera JP, Thomas PQ, Brickman JM, Gupta R, Mårtensson IL, Toresson H, Fox M, Wales JK, Hindmarsh PC, Krauss S, Beddington RS, Robinson IC. Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat Genet. 1998 Jun;19(2):125-33. PMID: 9620767
