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Kinase mutations in human disease: interpreting genotype–phenotype relationships

Nature Reviews Genetics volume 11, pages 60–74 (2010)Cite this article

Subjects

Key Points

  • Protein kinases comprise one of the largest families of evolutionarily related proteins.

  • Mutations in kinase genes underlie many human diseases, particularly developmental and metabolic disorders, as well as certain cancers.

  • We have curated inherited germline kinase gene mutations and briefly review the relationship between kinase gene mutations and cancer phenotypes.

  • The distribution of mutations has helped define crucial functional domains of kinases, mutational hotspots across the kinase gene family and the relevance of evolutionarily mediated lineage-specific variations.

  • The identification of the range of phenotypes in a single kinase gene brings clinical insight into various germline disorders and cancers.

  • Genome-wide association studies are heralding a new wave of discoveries by expanding the involvement of kinase variants from rare syndromes to complex diseases.

  • Kinases comprise ∼20% of all putative drug targets, so defining phenotype−genotype relationships of kinases will help the development of future therapies.

Abstract

Protein kinases are one of the largest families of evolutionarily related proteins and comprise one of the most abundant gene families in humans. Here we survey kinase gene mutations from the perspective of human disease phenotypes and further analyse the structural features of mutant kinases, including mutational hotspots. Our evaluation of the genotype–phenotype relationship across 915 human kinase mutations — that underlie 67 single-gene diseases, mainly inherited developmental and metabolic disorders and also certain cancers — enhances our understanding of the role of kinases in development, kinase dysfunction in pathogenesis and kinases as potential targets for therapy.

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Figure 1: Generic catalytic domain of protein kinases depicting subdomain structure and function.
Figure 2: Genetic pleiotropy.
Figure 3: Structural distribution of kinase mutations.

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Acknowledgements

P.L. is supported by the Canadian Institutes of Health Research (CIHR) Scriver Family M.D./Ph.D. studentship award and the Heart and Stroke Foundation of Ontario Vascular Training Program. R.A.H. holds the Edith Schulich Vinet Canada Research Chair (Tier I) in Human Genetics and the Jacob J. Wolfe Distinguished Medical Research Chair. This work was supported by operating grants from the Heart and Stroke Foundation of Ontario (NA 6,018), the Canadian Institutes for Health Research (MOP 13,430 and 79,533), the Jean Davignon Distinguished Cardiovascular-Metabolic Research Award (Pfizer, Canada) and Genome Canada through the Ontario Genomics Institute. N.J.S. and A.T. are supported in part by the Scripps Translational Science Institute Clinical Translational Science Award (NIH U54RR02504-01). A.T. is also supported in part by a Scripps Dickinson Fellowship. We thank Natarajan Kannan for providing an earlier version of Figure 1.

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Authors and Affiliations

  1. Robarts Research Institute and Departments of Medicine and Biochemistry, Schulich School of Medicine and Dentistry, University of Western Ontario, London, N6A 5C1, Ontario, Canada

    Piya Lahiry & Robert A. Hegele

  2. Scripps Genomic Medicine, Scripps Research Institute, La Jolla, 92037, California, USA

    Ali Torkamani & Nicholas J. Schork

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  1. Piya Lahiry
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Correspondence to Robert A. Hegele.

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Supplementary information

Supplementary Table 1

Inherited kinasopathies and their germline kinase mutation according to organ system involvement (PDF 274 kb)

Supplementary Table 2

Selected kinases associated with cancer and related findings in induced mutant animal models (PDF 290 kb)

Related links

Related links

DATABASES

OMIM

Carney syndrome

CFC syndrome

CML

Pfeiffer syndrome

FURTHER INFORMATION

Robert Hegele's homepage

1000 Genomes

Catalogue of Somatic Mutations in Cancer (COSMIC)

Kinase.com

Kinase Pathway Database

Kinase Sequence Database

KinMutBase

Kinweb Kinase Database

Multiple endocrine neoplasia type 2 (MEN2) RET database

Protein Kinase Resource

Protein Structure Initiative

The Cancer Genome Atlas

Glossary

Amino acids

Amino acids contain a basic amino (NH2) group, an acidic carboxyl (COOH) group and a side chain attached to an alpha carbon atom. The 20 amino acids can be classified based on the charge of their side chain, which can be neutral non-polar, neutral polar, acidic or basic.

Apoptosis

The process of programmed cell death that does not involve the release of harmful substances into the surrounding area. It has crucial function in division and differentiation by eliminating cells that are unnecessary for appropriate embryonic development.

Genetic pleiotropy

The effect of a single gene on multiple phenotypic traits. The underlying mechanism is related to the effects of the gene product on various targets.

Locus heterogeneity

This occurs when a phenotype is caused by mutations at more than one gene locus, which suggests that the products of the genes belong to the same metabolic pathway.

Mutational hotspots

A region in which the frequency of mutation is greater than expected, owing to specific structural and/or functional features of the protein or gene.

Kinome

The set of protein kinases in the genome of an organism.

Kinasopathy

A clinical phenotype that is caused by germline mutations in the kinase domain of functional proteins that lead to a loss-of-function or gain-of-function of the protein.

Myasthenia

A general term for an inherited neuromuscular disorder characterized by fluctuating muscle weakness and fatiguability that is often caused by one of several types of functional molecular defects at the neuromuscular junction.

Polycythemia vera

A blood disorder in which the bone marrow overproduces red blood cells (and sometimes other blood components). The resulting increase in blood viscosity can lead to health problems, especially enhanced blood clotting.

Tumour suppressor

A molecule that inhibits uncontrolled cell growth such that its loss- or reduction-of-function mutation favours the formation of tumours.

Proto-oncogene

A gene that promotes the specialization and division of cells; however, when it is mutated or expressed at high levels, it causes abnormal cellular growth.

Neuroblastoma

A childhood cancer derived from immature neurons of the sympathetic nervous system.

Common neutral mutation

A non-synonymous SNP present in at least 1% of the human population that is either overtly neutral or not known to influence disease in appreciable ways.

Allosteric interaction

In an enzyme with at least two binding sites (an active site and another binding site that binds an allosteric effector), the binding of an allosteric effector alters the structure of the enzyme and increases or decreases catalytic activity.

Ultra-conserved residue

An amino acid in a protein that has virtually 100% sequence identity across many species spanning hundreds of millions of years of evolution, suggesting that it has some essential role(s) in ontogeny and development.

'Gatekeeper' residue

A residue in the ATP-binding site of a protein kinase that controls the access of ATP or ATP-mimetic inhibitors to the binding pocket.

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Lahiry, P., Torkamani, A., Schork, N. et al. Kinase mutations in human disease: interpreting genotype–phenotype relationships. Nat Rev Genet 11, 60–74 (2010). https://doi.org/10.1038/nrg2707

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