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Understanding Brain Function Through Study of Inherited Traits in Humans
Summary: Louis Ptáček is interested in identifying genes that cause diseases of the nervous system and studying both the normal and mutant proteins encoded by some of these genes. Study of these rare, single-gene disorders may yield insights into common and complex diseases. His goal is to understand aspects of normal brain function, including human sleep behavior, and the molecular basis of diseases such as epilepsy and migraine headache.
Ion Channel Diseases
Some of the most common diseases in humans occur intermittently in people who are otherwise healthy and active. Such disorders include migraine headache, epilepsy, and cardiac arrhythmias. All of these diseases have prominent genetic components. Difficulty in understanding disorders like epilepsy and migraine arises from the complexity of the clinical phenotypes and the genetic heterogeneity that is certain to exist. Therefore, early work in our lab was aimed at understanding the pathogenesis of rare monogenic disorders that are similar in their episodic nature.
We have identified and studied five ion channel genes that, when mutated, cause a group of muscle diseases that share many similarities with other episodic disorders, such as headache and epilepsy. These include the genes that encode sodium, calcium, potassium, and chloride channels. More recently, we have been extending this work to episodic disorders of the brain.
Andersen-Tawil Syndrome
Andersen-Tawil syndrome (ATS) is a disorder with periodic paralysis and cardiac arrhythmias. We found that mutations in a potassium channel gene (KCNJ2) are responsible for ATS in more than 70 percent of patients. Remarkably, ATS also has a developmental phenotype affecting the head and limbs. These findings include variable expression of the following: wide-set eyes, low-set ears, small chin, cleft palate, crooked or shortened digits of hands and feet, and short stature.
The identification of KCNJ2 as an ATS gene extends the work from channels in electrical diseases and demonstrates a role for this ion channel in developmental processes. We have used our knowledge of the expression pattern of KCNJ2 (widely expressed, including in brain) to define interesting neurocognitive and dental phenotypes in ATS patients and to broaden the spectrum of the recognized clinical disorder. We have also generated animal models of some ATS mutations and, after characterizing the phenotypes in these mice, we can begin to study the developmental and other aspects of this disease in vivo.
Not all Episodic Diseases Result from Ion Channel Mutations
Ion channel disorders are now recognized not only in muscle but also in heart and brain. Interestingly, there are still other Mendelian episodic diseases that have not been characterized at a molecular level.
The familial paroxysmal dyskinesias are a group of overlapping clinical phenotypes that segregate in families. We recently cloned a gene for paroxysmal nonkinesigenic dyskinesia (PNKD). Rather than being a channel, the PNKD gene encodes a novel protein with homology to enzymes important for glutathione-coupled detoxification in a stress response pathway. We have now generated mice carrying the mutant human gene. These mice manifest a disorder very similar to the human disease and are enabling work to elucidate the role of this protein in brain and dysfunction of the mutant protein in PNKD. Since ion channels have been the major target for development of migraine and epilepsy drugs, non–channel proteins encoded by these genes, such as the one causing PNKD, may provide novel targets for development of a new class of treatments for episodic disorders.
We have also localized genes causing a familial, adult-onset myoclonic epilepsy to chromosome 8 and an epilepsy and movement-induced movement disorder to chromosome 16cen. Identification of these genes and study of the encoded proteins will lead to insights into the electrical excitability of neurons and the brain. (A grant from the National Institutes of Health provided partial support for some of these projects.)
Human Sleep Behavior
Large variations exist among all people with regard to preferred sleep and wake times, in a spectrum from morning larks to night owls. Genetic clues from Mendelian sleep variants may shed light on common genetic variants that contribute to human sleep preferences. Advanced sleep-phase syndrome (ASPS) is a common phenomenon in aging individuals. In this syndrome, people fall asleep and wake earlier than desired and earlier than they did when they were younger. The basis of ASPS is not known.
We have recently identified a Mendelian circadian rhythm trait resulting from a short circadian period. This syndrome, familial advanced sleep-phase syndrome (FASPS) is similar to the ASPS of aging except that it occurs in the young, is transmitted as a Mendelian trait, and is a more dramatic advance of the sleep time preference (extreme "morning larks"). In collaboration with Ying-Hui Fu (University of California, San Francisco), we have mapped and cloned five genes responsible for this trait in FASPS pedigrees. One gene, hPER2, is a homolog of the Drosophila period gene. The mutation occurs at a serine residue (S662) in a location that we have shown to be within the binding site of casein kinase I, an enzyme that phosphorylates PER2. A second gene encoding casein kinase Iδ (CKIδ) also harbors an FASPS mutation. This mutation of CKIδ leads to hypophosphorylation of PER2 in vitro. Moreover, phosphorylation of PER2 S662 leads to a hierarchical phosphorylation cascade of downstream serines by CKI. Further work is directed at identifying other substrates and establishing which of these are important in circadian regulation.
Mouse models of the Per2 and CKIδ mutations have been generated and show phenotypes identical to that seen in human FASPS. These mice, which have allowed in vivo study of the functional consequences of these mutations at a basic molecular level, have revealed some surprises and led us to modify existing models of circadian function.
In collaboration with Christopher Jones (University of Utah), we have collected a large number of FASPS families that are being investigated for mutations in hPER2, CKIδ, and other circadian rhythm candidate genes. Depression appears to cosegregate with the FASPS phenotype in some families. Remarkably, one family, studied in collaboration with Robert Shapiro (University of Vermont), has FASPS, asthma, and migraine with aura. It is not clear yet whether the asthma and migraine are coincidental or associated with FASPS in this family. Through study of such families, we hope to learn more about the human clock and its relationships to the clocks of other organisms and to potential roles of circadian genes in noncircadian systems.
Complex Episodic Disorders
Identifying genes that cause complex, polygenic disorders such as epilepsy and migraine is much more difficult than cloning genes causing Mendelian diseases. Epilepsy and migraine share many features with the channelopathies described here. These data suggest that there may be some similarities between the physiological basis of migraine, epilepsy, and rare, monogenic, episodic nervous system disorders.
Electrophysiological abnormalities result from the ion channel mutants mentioned above. It is likely that more-subtle abnormalities resulting from normal variations in ion channels (and related proteins) among normal people lead to small variations in muscle and nerve excitability. Although not disease-causing alone, such variations in neurons may lead, for example, to an increased or decreased predisposition to, or risk of, seizures.
We plan to extend the information regarding the molecular and physiological basis of rare monogenic disorders to polygenic traits, including migraine headache and epilepsy. Characterization of these monogenic disorders should provide clues about candidate genes that may be involved in clinically and genetically complex disorders. Examination of such candidates in DNA from a large, population-based collection of epilepsy and headache patients may identify genetic contributions to these complex disorders.
In summary, genetic approaches to neurologic diseases and behavioral phenotypes have made great progress in the past decade. Such discoveries are leading to insights not only into disease pathophysiology but also into normal function of the nervous system and normal variation in the population. More recently, the genetic contributions to human behavior have begun to be elucidated. Ultimately, such knowledge will lead to better diagnosis and treatment of patients with neurological diseases.
Last updated: April 4, 2007
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