Monogenic disorders in endocrinology and diabetes

Professor Richard C Trembath

University of Leicester

Summer School 15-18 July 2003
University of Manchester, Hulme Hall, Manchester, UK

The Human Genome Project has identified 30-35,000 transcripts of which only 2-3,000 have thus far been characterised. Medical molecular genetic studies have proven an exceptionally powerful approach to unravelling pivotal disease pathways through the identification of human mutations. These studies have confirmed the role of biological candidates for disease and revealed entirely novel genes whose protein products are required in key pathways for development or maintenance of initial structures. Perhaps less widely recognised the study of monogenic (single gene) disorders has also uncovered a number of complex mechanisms of disease causation. The paradigm of one gene, one protein, one disease has been fractured. Excellent examples of complex genetic mechanisms contributing to causation of endocrine disorders abound.

These concepts will be illustrated through recent studies of partial lipodystrophy (Dunnigan-Kobberling), an autosomal dominant disorder characterised by regional loss of subcutaneous fat and insulin resistance and due to heterozygous mutation of the nuclear envelope protein, lamin A/C. Surprisingly, no fewer than eight medical disorders have been shown to be allelic to LMNA [1,2,3]. Albright Hereditary Osteodystrophy (AHO) may be associated with hormone resistance, dependent upon the parental origin of a GNAS mutation. Studies of the GNAS locus, encoding the G protein stimulating sub unit [4], have revealed multiple transcripts generated by increasingly complex genomic organisation that are subject to imprinting.

Techniques for gene discovery in human monogenic disease are now well established and facilities for such experiments are widely accessible. Genome based analysis has become a cost effective approach and typically has superseded candidate gene analysis in disease locus identification. The principal limiting step remains access to sufficient and necessary human material (biological reagents including DNA, RNA and tissue specimens). Many groups have recently exploited the power of mapping autosomal recessive disease loci, by investigating consanguineous partnerships with affected offspring. Autozygosity (homozygosity) mapping will be illustrated, but such studies have also revealed complex inheritance patterns including tri-allelic and digenic disorders demonstrating a requirement for protein interaction in disease causation [5,6].

References:

1. Lloyd DJ, Trembath RC, Shackleton S. A novel interaction between lamin A and SREBP1: implications for partial lipodystrophy and other laminopathies. Hum Mol Genet. 2002 Apr 1;11(7):769-77.
2. Shackleton S, Lloyd DJ, Jackson SN, Evans R, Niermeijer MF, Singh BM, Schmidt H, Brabant G, Kumar S, Durrington PN, Gregory S, O'Rahilly S, Trembath RC. LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nat Genet. 2000 Feb;24(2):153-6.
3. Mounkes LC, Kozlov S, Hernandez L, Sullivan T, Stewart CL. A progeroid syndrome in mice is caused by defects in A-type lamins. Nature. 2003 May 15;423(6937):298-301
4. Aldred MA, Trembath RC. Activating and inactivating mutations in the human GNAS1 gene. Hum Mutat. 2000 Sep;16(3):183-9
5. Katsanis N, Ansley SJ, Badano JL, Eichers ER, Lewis RA, Hoskins BE, Scambler PJ, Davidson WS, Beales PL, Lupski JR. Triallelic inheritance in Bardet-Biedl syndrome, a Mendelian recessive disorder. Science. 2001 Sep 21;293(5538):2256-9.
6. Savage DB, Agostini M, Barroso I, Gurnell M, Luan J, Meirhaeghe A, Harding AH, Ihrke G, Rajanayagam O, Soos MA, George S, Berger D, Thomas EL, Bell JD, Meeran K, Ross RJ, Vidal-Puig A, Wareham NJ, O'Rahilly S, Chatterjee VK, Schafer AJ. Digenic inheritance of severe insulin resistance in a human pedigree. Nat Genet. 2002 Aug;31(4):379-84.)

The opinions expressed in this paper are those of the speaker and do not necessarily reflect the views of the Society

Revised: 04-Sep-2003