Louis Ptáček: Difference between revisions

In 1982, Louis Ptáček earned his [[Bachelor of Science]] degree in [[mathematics]] from the [[University of Wisconsin–Madison|University of Wisconsin-Madison]]. In 1986, he received his [[Doctor of Medicine]] degree from the [[University of Wisconsin–Madison|University of Wisconsin-Madison]] Medical School.<ref name=":0">{{Cite web|url=http://www.neugenes.org/louisptacek.htm|title=Neurogenetics: Louis Ptacek|website=www.neugenes.org|access-date=2017-04-11}}</ref> During his neurology residency at [[University of Utah]], he met a 28-year-old female patient who was suffering from [[Periodic paralysis|sporadic paralysis]], that inspired his current interest in the research of [[Genetic disorder|genetic diseases]] and episodic disorders research. In 1991, he discovered that a mutation in a gene ([[Nav1.4|SCN4A]]) that coded for a muscle cell [[sodium channel]] caused the patient’spatient's condition, [[hyperkalemic periodic paralysis]]. As the first channel was discovered to cause human disease, this human [[skeletal muscle]] sodium channel prevented the muscle from proper contractions.<ref name=":1" /><ref>{{Cite journal|last=Sakoda|first=S.|last2=Nakagawa|first2=M.|last3=Arimura|first3=Y.|last4=Arimura|first4=K.|last5=Osame|first5=M.|date=1997-12-01|title=[Familial hyperkalemic periodic paralysis: a brief review of the adult human skeletal muscle sodium channel and the application of LA-PCR to the SCN4A gene analysis]|url=https://www.ncbi.nlm.nih.gov/pubmed/9436446|journal=Nihon Rinsho. Japanese Journal of Clinical Medicine|volume=55|issue=12|pages=3253–3258|issn=0047-1852|pmid=9436446}}</ref> This invoked a series of discoveries of mutant ion channel genes whichthat constructed the framework for studying similar diseases, which Ptáček calls “"[[Channelopathy|channelopathies]].”"<ref name=":4">{{Cite web|url=http://profiles.ucsf.edu/louis.ptacek|title=UCSF Profiles|website=profiles.ucsf.edu|language=en|access-date=2017-04-12}}</ref>

Ptáček began his research on episodic [[Neurological disorder|neurological diseases]] by cloning and identifying genes that were responsible for [[periodic paralysis]] and non-dystrophic [[myotonia]].<ref name=":0" /> His research focuses on determining episodic disorders of the [[muscle]], [[heart]], and [[brain]], and found that many episodic diseases result from mutations in the electrical signaling of cell membranes.<ref name=":2">{{Cite web|url=http://keck.ucsf.edu/neurograd/faculty/ptacek.html|title=Neuroscience Graduate Program|website=keck.ucsf.edu|access-date=2017-04-12}}</ref> He had a large role in discovering that [[hyperkalemic periodic paralysis]], [[paramyotonia congenita]], [[Andersen–Tawil syndrome|Andersen-Tawil syndrome]], and [[thyrotoxic periodic paralysis]] are caused by mutations in genes encoding for [[Voltage-gated ion channel|voltage gated ion channels]].<ref name=":2" />

==== Andersen-Tawil syndrome (ATS) ====

His current research mainly focuses on identifying the genes involved with [[Andersen–Tawil syndrome|Andersen-Tawil syndrome]] (ATS). Ptáček's lab have identified [[Kir2.1|KCNJ2]] mutations to be potentially responsible for this syndrome, but due to the intrafamilial variability among the mutations, they hope to identify and characterize this gene further.<ref>{{Cite journal|last=Nguyen|first=Hoai-Linh|last2=Pieper|first2=Gerard H.|last3=Wilders|first3=Ronald|date=2013-12-05|title=Andersen-Tawil syndrome: clinical and molecular aspects|url=https://www.ncbi.nlm.nih.gov/pubmed/24383070|journal=International Journal of Cardiology|volume=170|issue=1|pages=1–16|issn=1874-1754|pmid=24383070|doi=10.1016/j.ijcard.2013.10.010}}</ref> Thus far, Ptáček and his colleagues have identified six disease-causing [[Mutation|mutationsmutation]]s, five of which are [[Muller's morphs|dominant negative]] mutations that mask the [[Wild type|wild-type]] [[allele]], resulting in a loss-of-function of that gene.<ref name=":2" /> With his continued research on ATS, Ptáček has discovered and identified additional phenotypic diagnostic criteria for ATS using skeletal and dental findings.<ref>{{Cite journal|last=Sansone|first=Valeria|last2=Tawil|first2=Rabi|date=2007-04-01|title=Management and treatment of Andersen-Tawil syndrome (ATS)|url=https://www.ncbi.nlm.nih.gov/pubmed/17395133|journal=Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics|volume=4|issue=2|pages=233–237|doi=10.1016/j.nurt.2007.01.005|issn=1933-7213|pmid=17395133|doi-access=free}}</ref> Additionally, he has identified other markers of the KCNJ2 channel mutation's including its [[Electrocardiography|ECG]] outputs' [[T wave|T-Wave]] and [[U wave|U-Wave]] patterns in order to provide more accurate differential diagnosis from [[Long QT syndrome|Long QT Syndrome]].<ref>{{Cite journal|last=Kukla|first=Piotr|last2=Biernacka|first2=Elzbieta K.|last3=Baranchuk|first3=Adrian|last4=Jastrzebski|first4=Marek|last5=Jagodzinska|first5=Michalina|date=2014-08-01|title=Electrocardiogram in Andersen-Tawil syndrome. New electrocardiographic criteria for diagnosis of type-1 Andersen-Tawil syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/24827800|journal=Current Cardiology Reviews|volume=10|issue=3|pages=222–228|doi=10.2174/1573403X10666140514102528|issn=1875-6557|pmc=4040873|pmid=24827800}}</ref>

Ptáček, with a team of collaborators, hypothesized that [[thyrotoxic periodic paralysis]] may be a case of channelopathy and can arise from ion channel mutations that display symptoms with [[hyperthyroidism]]. In January of 2010, they discovered a gene that encodes [[Kir2.6]], a novel inwardly rectifying potassium [[Protein channel|channel]]. This protein channel, highly similar to [[Kir2.2]], is transcriptionally regulated by the [[Thyroid hormones|thyroid hormone]] and expressed in skeletal muscles. Kir2.6 mutations, found in one third of unrelated TPP patients in the initial study, affect muscle membrane excitability and can lead to periodic paralysis.<ref>{{Cite web|url=https://www.ucsf.edu/news/2010/01/4340/periodic-paralysis-study-reveals-gene-causing-disorder|title=Periodic paralysis study reveals gene causing disorder|website=UC San Francisco|language=en|access-date=2017-04-12}}</ref>

In 1999, Ptáček was introduced to a family in [[Utah]] who had a very distinct sleep schedule. After analyzing the family's [[Pedigree chart|pedigree]] and identifying individuals with a genetic basis for an advanced sleep phase, he later coined the term familial advanced sleep phase syndrome (FASPS).<ref name=":1">{{Cite news|url=http://www.hhmi.org/scientists/louis-j-ptacek|title=Louis J. Ptáček, MD {{!}} HHMI.org|work=HHMI.org|access-date=2017-04-12|language=en}}</ref> The disorder is characterized by around ana four -hour phase advance, causing individuals to sleep from approximately 7:30 pm to 4:30 am.

In 2001, Ptáček and his colleagues localizeddiscovered the mutation in the [[Dominance (genetics)|autosomal dominant]] FASPSallele gene.responsible Theyfor identifiedFASPS. theThe [[point mutation]] fromis in the hPer2 gene, and results in a [[serine]] to [[glycine]] at [[amino acid]] sitesubstitution at position 662. Specially, this mutation occurs in the CK1ε binding region of the [[CaseinPER2]] kinaseprotein, 1and isoformcauses epsilon|caseinPER2 kinaseto 1<math>\epsilon</math>be [[Phosphorylation|hypophosphorylated]] bindingin that region, allowing it to be more stable and enter the nucleus faster. This results in quicker suppression of the genehPer2 [[PER2Transcription (biology)|hPer2gene transcription]], causing hypophosphorylation and alteringshortening the individual's circadian period inand theseleading affectedto FASPS individualssymptoms.<ref name=":3" />

Ptáček, withand his colleagues, have also found that a mutation in hPer2 is not the only gene that causes FASPS when mutated, and current research is exploring other sporadic cases of FASPS to identify new mutations that contribute to the syndrome.<ref name=":5">{{Cite web|url=http://www.neugenes.org/circadian.htm|title=Circadian|website=www.neugenes.org|access-date=2017-04-12}}</ref>

Currently, Ptáček's lab is interested in studying the genetic basis of [[Delayed sleep phase disorder|familial delayed sleep phase syndrome]] (FSDPS), which is a condition indicatedcharacterized by a delay in the sleep cycle where affected individuals fall asleep late in the night and wake up late in the morning or afternoon. Thus far, little is known about FDSPS although it is thought to be a heritable condition relatively common in adolescents andwith symptoms typically recedingsubsiding with age. However, some individuals are affected by FSDPS throughout their lives.<ref name=":5" />