Rare Diseases

What are rare diseases?

Currently > 3000 single gene disorders are annotated in the Online Mendelian Inheritance in Man (OMIM) database, each affecting a particular gene and its associated protein. This number is estimated to reach over 7000, as new genotypes are being uncovered and defined. These disorders are often referred to as rare or orphan diseases, because of their relatively low incidence* individually (*defined as affecting < 5 in 10000 in the EU and < 200000 patients in the US), though collectively afflicting 1-3% of the global population.

Why study rare diseases?

Fewer than 5% of known rare diseases have FDA-approved drug therapies. Progress is limited by our poor understanding of the structure and function of the associated proteins as well as the effects of disease mutations. In addition, there are estimated to be over 4000 monogenic disorders for which the causative gene has yet to be identified. Rare diseases present therefore a significant unmet medical need in disease diagnosis, management and treatment.

SGC and rare diseases

85% of known single gene disorders are caused by genetic variations in the exomic space, rendering the encoded proteins the relevant target for investigation. To understand disease phenotypes and to advance the development of new treatments, we are applying structural and chemical biology approaches to the study of a wide range of rare diseases with particular interest in the following areas:

Genomic variation & disease

Data linking genes to diseases is expanding rapidly, in hand with the ubiquity of exome and genome sequencing and large-scale association studies. The amount of data far outstrips the ability to interpret and utilize these links; as a result, research tends to focus on genes and pathways that are already familiar. Our research aims at understanding the functions of less-familiar genes and the molecular consequences of disease-linked variants. In collaboration with geneticists and clinicians, we purify and study the protein products of disease-linked genes by crystallography, functional studies and immunochemistry. We anticipate that this research will deepen our understanding of disease processes and offer new avenues for therapy.

Inborn Errors of Metabolism

The Metabolism and Organelle Biogenesis (MOB) group performs biochemical and structural characterization on metabolic enzymes and protein-protein complexes linked with a subset of ~400 rare genetic diseases, known as inborn errors of metabolism (IEM). With a repertoire to date of > 50 crystals structures and 120 recombinant proteins, we establish a protein-centric, collaborative network with clinicians, geneticists and drug developers, to understand genetic defects at the protein level and develop small molecule therapies. Our recent highlight includes the structural elucidation of a family of vitamin B12 processing proteins , mutations of which lead to defects in the assembly of the essential cofactor into two client enzymes.

Membrane Proteins & Disease

We study structures of proteins that are embedded in the lipid bilayers of cells. These proteins have partially hydrophobic surfaces and are therefore relatively unstable and difficult to purify and study. There are over 3000 such proteins in the human proteome and they contribute to many rare diseases. One such rare disease is the premature ageing disease Hutchinson-Gilford Progeria Syndrome (HGPS), found in 1 new-born in 4 million. Children with HGPS age very rapidly and normally die in their teens from atherosclerosis.   HGPS and related progeroid diseases are caused by incorrect processing of lamin proteins in the cell nucleus by a nuclear membrane embedded enzyme called ZMPSTE24. We recently solved the structure of ZMPSTE24 (Quigley et al., Science, 3013),  revealing a completely unexpected structure. ZMPSTE24 forms a huge chamber inside the nuclear membrane where the tail of prelamin A is processed. Progeroid diseases are caused by mutations in the lamin gene or in ZMPSTE24 which prevent processing and this structure shows how mutations can cause these diseases (see figure).

Rare cancers & Developmental Disorders

Mutations in protein kinases are commonly associated with rare human cancers as well as many developmental disorders, including inflammatory and neurological conditions. Deregulated signalling is a potential target for small molecule kinase inhibitors. One of the most debilitating examples is fibrodysplasia ossificans progressiva (FOP), a rare congenital disorder of heterotopic bone formation resulting from activating mutations in the BMP receptor ACVR1. We have identified novel inhibitor molecules against ACVR1 and are now collaborating with patient groups, clinicians and other scientists to better understand the disease mechanism and to establish more potent and selective inhibitors for preclinical development.

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