Louis Ptáček
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Louis Ptáček is an American neurologist and professor of Czech origin. He contributed to the field of
genetics Genetics is the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) It is an important branch in biology because heredity is vital to organisms' evolution. Gregor Mendel, a Moravian Augustinians, Augustinian ...
and
neuroscience Neuroscience is the scientific study of the nervous system (the brain, spinal cord, and peripheral nervous system), its functions, and its disorders. It is a multidisciplinary science that combines physiology, anatomy, molecular biology, ...
. He was also an HHMI investigator from 1997 to 2018. His chief areas of research include the understanding of inherited Mendelian disorders and
circadian rhythm A circadian rhythm (), or circadian cycle, is a natural oscillation that repeats roughly every 24 hours. Circadian rhythms can refer to any process that originates within an organism (i.e., Endogeny (biology), endogenous) and responds to the env ...
genes. Currently, Ptáček is a neurology professor and a director of the Division of Neurogenetics in University of California, San Francisco, School of Medicine. His current investigations primarily focus on extensive clinical studies in families with hereditary disorders, which include identifying and characterizing the genes responsible for neurological variations.


Background and education

In 1982, Louis Ptáček earned his
Bachelor of Science A Bachelor of Science (BS, BSc, B.S., B.Sc., SB, or ScB; from the Latin ') is a bachelor's degree that is awarded for programs that generally last three to five years. The first university to admit a student to the degree of Bachelor of Scienc ...
degree in
mathematics Mathematics is a field of study that discovers and organizes methods, Mathematical theory, theories and theorems that are developed and Mathematical proof, proved for the needs of empirical sciences and mathematics itself. There are many ar ...
from the
University of Wisconsin-Madison A university () is an institution of tertiary education and research which awards academic degrees in several academic disciplines. ''University'' is derived from the Latin phrase , which roughly means "community of teachers and scholars". Uni ...
. In 1986, he received his
Doctor of Medicine A Doctor of Medicine (abbreviated MD, from the Latin language, Latin ) is a medical degree, the meaning of which varies between different jurisdictions. In the United States, and some other countries, the ''MD'' denotes a professional degree of ph ...
degree from the
University of Wisconsin-Madison A university () is an institution of tertiary education and research which awards academic degrees in several academic disciplines. ''University'' is derived from the Latin phrase , which roughly means "community of teachers and scholars". Uni ...
Medical School. During his neurology residency at
University of Utah The University of Utah (the U, U of U, or simply Utah) is a public university, public research university in Salt Lake City, Utah, United States. It was established in 1850 as the University of Deseret (Book of Mormon), Deseret by the General A ...
, he met a 28-year-old female patient who was suffering from sporadic paralysis, that inspired his current interest in the research of
genetic diseases A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders are ...
and episodic disorders. In 1991, he discovered that a mutation in a gene ( SCN4A) that coded for a muscle cell
sodium channel Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell (biology), cell's cell membrane, membrane. They belong to the Cation channel superfamily, superfamily of cation channels. Classific ...
caused the patient's condition, hyperkalemic periodic paralysis. As the first channel was discovered to cause human disease, this human
skeletal muscle Skeletal muscle (commonly referred to as muscle) is one of the three types of vertebrate muscle tissue, the others being cardiac muscle and smooth muscle. They are part of the somatic nervous system, voluntary muscular system and typically are a ...
sodium channel prevented the muscle from proper contractions. This invoked a series of discoveries of mutant ion channel genes that constructed the framework for studying similar diseases, which Ptáček calls " channelopathies." In 1999, Christopher Jones, a neurologist from University of Utah who specializes in sleep disorders, contacted Ptáček to characterize a family of early risers and find the
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
s associated with this
phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...
. He and his partner, Ying-Hui Fu, in collaboration with Jones, have identified multiple genes, such as hPer2, that are responsible for
familial advanced sleep phase syndrome Advanced Sleep Phase Disorder (ASPD), also known as the advanced sleep-phase type (ASPT) of circadian rhythm sleep disorder, is a condition that is characterized by a recurrent pattern of early evening (e.g. 7-9 PM) sleepiness and very early morn ...
(FASPS). This discovery prompted Ptáček to continue his research on
circadian A circadian rhythm (), or circadian cycle, is a natural oscillation that repeats roughly every 24 hours. Circadian rhythms can refer to any process that originates within an organism (i.e., endogenous) and responds to the environment (is entrai ...
genes.


Episodic diseases


Channelopathies

Ptáček began his research on episodic
neurological diseases Neurological disorders represent a complex array of medical conditions that fundamentally disrupt the functioning of the nervous system. These disorders affect the brain, spinal cord, and nerve networks, presenting unique diagnosis, treatment, and ...
by cloning and identifying genes that were responsible for periodic paralysis and non-dystrophic
myotonia Myotonia is a symptom of a small handful of certain neuromuscular disorders characterized by delayed relaxation (prolonged contraction) of the skeletal muscles after voluntary contraction or electrical stimulation, and the muscle shows an abnor ...
. His research focuses on determining episodic disorders of the
muscle Muscle is a soft tissue, one of the four basic types of animal tissue. There are three types of muscle tissue in vertebrates: skeletal muscle, cardiac muscle, and smooth muscle. Muscle tissue gives skeletal muscles the ability to muscle contra ...
,
heart The heart is a muscular Organ (biology), organ found in humans and other animals. This organ pumps blood through the blood vessels. The heart and blood vessels together make the circulatory system. The pumped blood carries oxygen and nutrie ...
, and
brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
, and found that many episodic diseases result from mutations in the electrical signaling of cell membranes. He had a large role in discovering that hyperkalemic periodic paralysis,
paramyotonia congenita ''Paramyotonia congenita'' (PC) is a rare congenital autosomal dominant neuromuscular disorder characterized by "paradoxical" myotonia. This type of myotonia has been termed paradoxical because it becomes worse with exercise whereas classical my ...
, Andersen-Tawil syndrome, and thyrotoxic periodic paralysis are caused by mutations in genes encoding for voltage gated ion channels.


Andersen-Tawil syndrome (ATS)

His current research mainly focuses on identifying the genes involved with Andersen-Tawil syndrome (ATS). Ptáček's lab have identified 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. Thus far, Ptáček and his colleagues have identified six disease-causing
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
s, five of which are
dominant negative In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and ...
mutations that mask the
wild-type The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, " ...
allele An allele is a variant of the sequence of nucleotides at a particular location, or Locus (genetics), locus, on a DNA molecule. Alleles can differ at a single position through Single-nucleotide polymorphism, single nucleotide polymorphisms (SNP), ...
, resulting in a loss-of-function of that gene. With his continued research on ATS, Ptáček has discovered and identified additional phenotypic diagnostic criteria for ATS using skeletal and dental findings. Additionally, he has identified other markers of the KCNJ2 channel mutation's including its
ECG Electrocardiography is the process of producing an electrocardiogram (ECG or EKG), a recording of the heart's electrical activity through repeated cardiac cycles. It is an electrogram of the heart which is a graph of voltage versus time of ...
outputs' T-Wave and U-Wave patterns in order to provide more accurate differential diagnosis from
Long QT Syndrome Long QT syndrome (LQTS) is a condition affecting repolarization (relaxing) of the heart after a heartbeat, giving rise to an abnormally lengthy QT interval. It results in an increased risk of an irregular heartbeat which can result in fainti ...
.


Thyrotoxic periodic paralysis (TPP)

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 Hyperthyroidism is a endocrine disease in which the thyroid gland produces excessive amounts of thyroid hormones. Thyrotoxicosis is a condition that occurs due to elevated levels of thyroid hormones of any cause and therefore includes hyperth ...
. In January 2010, they discovered a gene that encodes Kir2.6, a novel inwardly rectifying potassium channel. This protein channel, highly similar to Kir2.2, is transcriptionally regulated by the
thyroid hormone File:Thyroid_system.svg, upright=1.5, The thyroid system of the thyroid hormones triiodothyronine, T3 and T4 rect 376 268 820 433 Thyroid-stimulating hormone rect 411 200 849 266 Thyrotropin-releasing hormone rect 297 168 502 200 Hypothalamus r ...
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.


Human sleep behavior


Familial advanced sleep phase syndrome (FASPS)

In 1999, Ptáček was introduced to a family in
Utah Utah is a landlocked state in the Mountain states, Mountain West subregion of the Western United States. It is one of the Four Corners states, sharing a border with Arizona, Colorado, and New Mexico. It also borders Wyoming to the northea ...
who had a very distinct sleep schedule. After analyzing the family's pedigree and identifying individuals with a genetic basis for an advanced sleep phase, he coined the term familial advanced sleep phase syndrome (FASPS). The disorder is characterized by around a four-hour phase advance, causing individuals to sleep from approximately 7:30 pm to 4:30 am. In 2001, Ptáček and his colleagues discovered the mutation in the
autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
allele responsible for FASPS. The
point mutation A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequences ...
is in the hPer2 gene, and results in a
serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − ...
to
glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid. Glycine is one of the proteinogenic amino acids. It is encoded by all the codons starting with GG (G ...
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
substitution at position 662. Specially, this mutation occurs in the CK1ε binding region of the
PER2 PER2 is a protein in mammals encoded by the ''PER2'' gene. ''PER2'' is noted for its major role in circadian rhythms. Discovery The ''per ''gene'' ''was first discovered using forward genetics in '' Drosophilla melanogaster'' in 1971. Mammali ...
protein, and causes PER2 to be hypophosphorylated in that region, allowing it to be more stable and enter the nucleus faster. This results in quicker suppression of the hPer2
gene transcription Transcription is the process of copying a segment of DNA into RNA for the purpose of gene expression. Some segments of DNA are transcribed into RNA molecules that can encode proteins, called messenger RNA (mRNA). Other segments of DNA are transc ...
, shortening the individual's circadian period and leading to FASPS symptoms. Ptáček and his colleagues have also found that 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.


Ongoing research

Currently, Ptáček's lab is interested in studying the genetic basis of familial delayed sleep phase syndrome (FSDPS), which is a condition characterized 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 with symptoms typically subsiding with age. However, some individuals are affected by FSDPS throughout their lives.


Awards and honors


Selected publications

# Toh KL, Jones CR, He Y, Eide EJ, Hinz WA, Virshup DM, Ptáček LJ, Fu Y-H
An hPer2 Phosphorylation Site Mutation in Familial Advanced Sleep-Phase Syndrome
Science. 2001;291:1040-1043. # Plaster, NM, Tawil R, Tristani-Firouze M, Canun S, Bendahhou S, Tsunoda A, Donaldson MR, Iannaccone ST, Brunt E, Barohn R, Clark J, Deymeer F, George AL, Fish FA, Hahn A, Nitu A, Ozdemir C, Serdaroglu P, Subramony S, Wolfe G, Fu Y-H, Ptáček LJ
Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen’s Syndrome
Cell. 2001, 105:511-519. # Xu Y, Padiath Q, Shapiro R, Jones CR, Wu SC, Saigoh N, Saigoh K, Ptáček LJ, Fu Y-H
Functional consequences of a CK1δ mutation causing familial advanced sleep phase syndrome
Nature. 2005: Vol. 434:640-644. # Jones CR, Campbell SS, Zone SE, Cooper F, DeSano A, Murphy PJ, Jones B, Czajkowski L, Ptáček LJ
Familial advanced sleep-phase syndrome: a short period circadian rhythm variant in humans.
Nat Med. 1999;5:1062-1065. # Padiath QS, Saigoh K, Schiffmann R, Asahara H, Koeppen A, Hogan K, Ptáček LJ, Fu YH
Lamin B1 duplications cause autosomal dominant leukodystrophy.
Nat Genet. 2006 Oct; 38(10):1114-23. # Xu Y, Toh KL, Jones CR, Shin JY, Fu YH, Ptáček LJ
Modeling of a human circadian mutation yields insights into clock regulation by PER2.
Cell. 2007 Jan 12; 128(1):59-70.


References

{{DEFAULTSORT:Ptacek, Louis American neurologists University of California, San Francisco faculty Brandeis University faculty Year of birth missing (living people) Living people Members of the National Academy of Medicine