br Genetics of Pain Sensitivity Pain is a distressing feelin
Genetics of Pain Sensitivity Pain is a distressing feeling often caused by unpleasant stimulation resulting in tissue damage, and is the most common reason for general practitioner consultations in the developed world. Geoff Woods (Cambridge, UK) presented the latest developments in the study of Mendelian disorders of pain sensitivity. These disorders result from a mutation at a single genetic locus that is inherited in families in a particular pattern. An individual might display insensitivity to pain, or conversely increased pain perception, depending on the consequence of the causative mutation. The aim is to attribute mutations to specific disorders by sequencing the DNA of affected families, enabling insight into the molecular mechanisms that lead to the disease phenotype. Many acquired pain syndromes occur through mutations in ion Dynasore that are expressed on nociceptors. Nociceptors are sensory neurons that detect stimuli that have the potential to cause tissue injury such as extremes of temperature, chemical irritants and mechanical damage. The exact function of a given nociceptor will depend on the type and distribution of ion channels that are expressed, and this heterogeneity enables an appropriate response to a range of sensory inputs. For example, voltage-gated sodium channels (Nav) allow extracellular Na+ to pass into the interior of the neuron, which can result in an action potential. In humans, mutations in the Nav1.7, encoded by SCN9A, can cause congenital insensitivity to pain if a null mutation prevents the passage of Na+ into the cell. Conversely, if an activating mutation is present, this results in Nav1.7 opening more easily allowing too many Na+ to pass into the cell. This can result in disorders such as inherited erythromelalgia (IEM), causing chronic pain in the hands and feet. Recent developments in drugs that selectively block Nav1.7 can elicit a reversal of the pain phenotype in humans with IEM. It is hoped that subtype-specific blockade of other sodium channels might prove an effective approach to treat a range of pain perception disorders.
Consequences of PPA2 Mutations In a session dedicated to metabolic and mitochondrial disorders, two talks focused on disorders associated with mutations in the mitochondrial inorganic pyrophosphatase (PPA2). PPA2 is an enzyme that catalyzes the hydrolysis of inorganic phyrophosphate (PPi) to two phosphate ions, resulting in the liberation of 19kJ. This reaction is coupled to many energetically unfavourable reactions to drive them to completion, for example in the metabolism of lipids. Mitochondria produce the majority of the energy required by a cell, and consequently contain ~90% of cellular PPi. Therefore mutations that affect the function of this enzyme can cause huge problems, especially in tissues that have high energy requirements such as the heart. Kit Doudney (Christchurch, New Zealand) presented data on four families with a spectrum of cardiomyopathy disorders. Next-generation sequencing technologies identified mutations in the PPA2 gene that were responsible for a number of neonatal cardiac-related medical conditions including lactic acidosis and heart failure. In one family with acute sensitivity to alcohol, two brothers died at 15 and 20years of age. Sequencing results revealed that both siblings had inherited compound mutations, one in the catalytic site and the other affecting a residue potentially involved in the dimerization of PPA2. Functional studies in E. coli demonstrated that this combination of mutations caused PPA2 to work inefficiently, with catalytic activity reduced by ~70%. However, this reduction is less than the 95% activity loss observed with purely catalytic mutations present in the majority of affected families. The small increase in PPA2 activity associated with the dimerizing proline228 mutation may explain the later age of onset associated with cardiac failure in this family. The surviving siblings also inherited these homoplastic sequence variants in PPA2, and were subsequently fitted with artificial pacemakers to counter cardiac arrhythmias. Anne Guimier (Paris, France), then presented data on two families with recurrent sudden unexpected death in infancy (SUDI). SUDI is the most common case of post-natal infant mortality in developed countries, although the underlying cause is largely unexplained. All babies from these families died of cardiac arrest at 4–20months. When post-mortem tissue was analyzed by whole exome sequencing, compound heterozygous missense variations in the PPA2 gene were identified. Both studies reveal new links with PPA2 and human disorders, which may have implications for undiagnosed individuals with mutations in this gene.