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  • Review Article
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Human monogenic disorders — a source of novel drug targets

Nature Reviews Genetics volume 7, pages 249–260 (2006)Cite this article

Key Points

  • Target selection and validation is a crucial first step in developing a drug against a given disease. Human genetic analysis is an important model for the identification and/or validation of novel therapeutic targets.

  • Monogenic disorders, involving rare high-penetrance mutations, comprise the most easily interpretable component of experimental human genetics. Because mutations alter the level of activity of gene products, they can be thought of as surrogates for perfectly targeted drugs, the job of which is to antagonize or agonize a given gene product.

  • Phenotypes of some monogenic disease states are of immediate relevance to major therapeutic programmes in the biotechnology and pharmaceutical sectors. The genetics of anti-disease states, such as low blood glucose or low plasma cholesterol, provides a novel approach to new target identification.

  • Among monogenic disorders that have understood molecular bases, many of the causal genes are 'druggable' using classical pharmaceutical methodologies. New chemistries will increase the fraction of the genome that is accessible to small molecular therapeutics.

  • Of the estimated 25,000 genes in the human genome repertoire, only approximately 1,500 have known monogenic disorders that are associated with high-penetrance mutations. Therefore, most of the genome remains to be characterized in terms of monogenic phenotypes. Some of these phenotypes are likely to be relevant to therapeutic developments for medically and commercially important diseases.

  • Ascertainment and molecular characterization of the complete monogenic human genome will require dedicated efforts in clinical genetics, bringing together medical descriptions of known and novel phenotypes with improved technological methods for gene discovery.

Abstract

The decrease in new drug applications and approvals over the past several years results from an underlying crisis in drug target identification and validation. Model organisms are being used to address this problem, in combination with novel approaches such as the International HapMap Project. What has been underappreciated is that discovery of new drug targets can also be revived by traditional Mendelian genetics. A large fraction of the human gene repertoire remains phenotypically uncharacterized, and is likely to encode many unanticipated and novel phenotypes that will be of interest to pharmaceutical and biotechnological drug developers.

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Figure 1: Characteristics of the human phenome.
Figure 2: Regulation of insulin secretion by the SUR1 receptor complex in pancreatic islet cells.
Figure 3: Mapping rare genetic disorders in founder or isolated populations.

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Acknowledgements

Thanks to V. McKusick and J. Amberger for data from the Online Mendelian Inheritance in Man. Thanks to M. Ludman, S. Dyack and D. Skidmore for valuable discussions of clinical genetics phenotypes. Thanks to P. Goldberg, R. Sherrington, S. Pimstone for discussions of therapeutic targets. Thanks to S. Chanda for logistic assistance. R.R.B. is supported by a Michael Smith Foundation for Health Research (MSFHR) Research Unit Infrastructure award. M.E.S. is supported by the IWK Health Centre, Capital District Health Authority and Dalhousie University Faculty of Medicine.

Author information

Authors and Affiliations

  1. British Columbia Cancer Research Centre, University of British Columbia, Vancouver, V5Z 1C3, British Columbia, Canada

    Ryan R. Brinkman

  2. Montreal Heart Institute Research Centre, University of Montreal, Montreal, H1T 1C8, Quebec, Canada

    Marie-Pierre Dubé

  3. Department of Medicine, University of Montreal,

    Guy A. Rouleau

  4. Department of Ophthalmology & Visual Sciences, Dalhousie University, Halifax, B3H 2Y9, Nova Scotia, Canada

    Andrew C. Orr

  5. Departments of Ophthalmology & Visual Sciences, Pediatrics and Psychiatry, Dalhousie University,

    Mark E. Samuels

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  1. Ryan R. Brinkman
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DATABASES

OMIM

α-synuclein

amyloid-β A4 precursor

butyrylcholinesterase

CCR5

circadian rhythm

CYP2D6

diabetes

EPOR

ERBB2

Fabry disease

favism

fibrillin 1

fructose intolerance

GHR

HOXA1

HOXA13

hyperalphalipoproteinaemia

hypertension

hypoglycaemia

IL2RA

IL2RG

ITGA2B

language disorders

leucine-rich repeat kinase 2

MC4R

microtubule-associated protein tau

obesity

oncogene DJ1

parkin

phenylketonuria

presenilin 1

presenilin 2

PTEN-induced kinase

TPMT

transthyretin

ubiquitin carboxylterminase esterase L1

FURTHER INFORMATION

Babelomics

Cystic Fibrosis Mutation Database

Eco-Economy Indicators web site

Frontiers in Bioscience Database of Gene Knockouts

International HapMap Project

LDLR Locus web site

Online Mendelian Inheritance in Man database

PubMed

Glossary

Haplotype mapping

A technique that involves the use of combinations of 'common' DNA polymorphisms to find blocks of association with phenotypic traits.

Humanized antibodies

Antibodies in which only the parts of antibody variable regions that mediate the contact to antigens have been grafted onto a human antibody framework by means of genetic engineering techniques.

Peptidomimetics

Compounds that are derived from peptides and proteins by structural modification using, for example, unnatural amino acids, conformational restraints, isosteric replacement and cyclization.

Pleiotropic

The phenomenon in which a single gene is responsible for several distinct and seemingly unrelated phenotypic effects.

Minor allele frequency

The frequency of the less common allele of a polymorphic locus. It has a value that lies between 0 and 0.5, and can vary between populations.

Endometriosis

A common medical condition in which the tissue lining the uterus (the endometrium) is found outside the uterus, typically affecting other organs in the pelvis.

Founder populations

Populations that that have been derived from a limited pool of individuals within the last 100 or fewer generations.

Compound heterozygosity

A situation in which an inidividual is heterozygous for two different mutations at the same locus.

Proband

A subject that is ascertained on the basis of phenotype; they are often used to identify affected families for genetic studies.

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Brinkman, R., Dubé, MP., Rouleau, G. et al. Human monogenic disorders — a source of novel drug targets. Nat Rev Genet 7, 249–260 (2006). https://doi.org/10.1038/nrg1828

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