Rare diseases

Mutations affecting critical proteins.

Exploring the Uncommon World of Rare Diseases

Rare diseases are caused by inherited or de novo genetic mutations and include cancers, metabolic diseases, cystic fibrosis, muscular dystrophy, cardiac arrhythmias, sickle cell anemia, and some forms of epilepsy. A rare disease affects fewer than 1-in-2,000 people (< 200,000 people in USA) with over 6,000 rare diseases affecting 300 million people worldwide, with diagnosis increasing due to cheap and widespread genetic testing.

Treatments include gene therapy or editing and faulty enzyme replacement. Rare diseases are also called orphan diseases as it can be slow and expensive to develop new drugs for very small patient populations.

Current diagnosis and treatments

for rare diseases

Understanding rare diseases

Mutations in ion channels can cause inherited ion channelopathies which underlie common or rare diseases. In general, the mutations can be loss or gain of function resulting in the clinical phenotype. Many rare diseases have few treatment options available, if any. Genetic treatments for rare diseases include exon-skipping small molecules and RNA drugs, as well as gene therapies to deliver replacement genes in viral vectors or correct faulty sequences using gene editing techniques (CRISPR, base, and prime editing). Faulty proteins can also be replaced (e.g. enzymes in Fabry, Gaucher, and Pompe disease) or their misfolding corrected with small molecules. Alternatively, pharmacological agents can be sought which selectively up or downregulate the action of the faulty protein and ion channels may hold the key to the treatment of at least some rare diseases. As rare diseases typically occur from birth and are diagnosed by genetic testing in young children, effective treatments have the potential to improve the quality and duration of life which offsets their high cost.

Ion channels

in rare diseases

Mutations in Na+ channels in human arrhythmia and epilepsy syndromes

Brugada syndrome is a rare but potentially fatal cardiac arrhythmia disorder associated with sudden cardiac arrest and death in young adults. Loss-of-function (LOF) mutations in the SCN5A gene which encodes the cardiac voltage-gated sodium channel, NaV1.5, are the most common cause of Brugada syndrome, accounting for up to 30% of occurrences in Caucasians. Other LOF mutations in CaV1.2 and TRPM4, and gain-of-function (GOF) mutations in voltage-gated potassium channels have also been identified.

Dravet syndrome is a catastrophic and pharmacoresistant childhood epilepsy disorder which is characterized by the onset of epileptic seizures within the first year of life and is accompanied by cognitive impairment, ataxia, psychomotor regression, and autism. In most cases, Dravet syndrome is caused by a de novo loss-of-function mutation in the SCN1A gene which encodes the NaV1.1 ion channel. In the brain, NaV1.1 is primarily located in inhibitory and thus when NaV1.1 activity is reduced, this leads to a reduction in inhibitory neurotransmission and thus hyperexcitability in the CNS resulting in epileptic seizures. One potential treatment option would be to enhance the action of NaV1.1 and thus restore inhibitory neurotransmission.

The spider venom peptide Hm1a enhanced peak amplitude and delayed fast inactivation of NaV1.1 and, with lower potency, NaV1.3 but not NaV1.2, 1.5 or 1.7 recorded on the Patchliner. This in turn rescues interneuron function in Dravet syndrome mice and may provide a viable therapeutic option to treat this epileptic condition.

Richards K.L, et al. PNAS. (2018)

Examples of ion channels and transporters involved in rare diseases

Brugada syndrome
NaV1.5, TRPM4, CaV1.2, HCN4, hERG (KV11.1)
Dravet syndrome
SCN2A-related disorders
Timothy syndrome
Cystic fibrosis
Duchenne muscular dystrophy and myotonia congenita
CLCN4-related neurodevelopmental disorder (CLCN4-NDD)
Sickle cell anemia
Gardos channel (SK4) and KCC transporter
Dent’s disease type 1
CLC-5 (antiporter)

An example of rare diseases: Decoding CLCN4

CLCN4-related conditions are exceptionally rare, affecting just over 120 individuals worldwide with a CLCN4 gene change. The CLCN4 gene encodes the CLC-4 protein, a Cl-/H+ exchanger primarily expressed in the brain and skeletal muscle. Within intracellular organelles, the CLC-4 protein plays a crucial role in ion homeostasis of endosomes and intracellular trafficking.

Learn more about CLCN4-related conditions.

Assay platforms for

rare disease research

Automated patch clamp,
transporter assays and bilayers

Automated patch clamp platforms are well suited to study ion channels involved in rare diseases. NaV channels can be recorded using the Port-a-Patch, Patchliner and SyncroPatch 384, to investigate the functional effect of genetic variants and potentially corrective pharmacological agents. Red blood cells can be used on the devices to investigate the effects of ion channels in disorders affecting these cells.

Transporters involved in rare diseases can be recorded on the SURFE2R N1 and at higher throughput on the SURFE2R 96 instruments and ion channels can be reconstituted into bilayers and recorded on the Orbit mini and Orbit 16 TC. Human iPSC-derived cardiomyocytes can be recorded on the CardioExcyte 96 and FLEXcyte 96 to investigate the effects of mutations on cardiomyocyte contractility and morphology.

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