Louis Ptáček

Louis Ptacek is an American neurologist and professor who contributed greatly to the field of genetics and neuroscience. His chief research include the understanding of inherited Mendelian disorders, and circadian rhythm genes. Currently, Ptacek 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 the identification and characterization of genes responsible for neurological variations, including extensive clinical studies on families with hereditary disorders.

Background and Education

In 1982, Louis Ptacek earned his Bachelor of Science degree in mathematics from the University of Wisconsin-Madison. In 1986, he received his Doctor of Medicine degree from the University of Wisconsin-Madison Medical School.^[1] During his neurology residency at University of Utah, he met a patient who was suffering from sporadic paralysis that inspired his current interest in genetic diseases and episodic disorders research. In 1991, he found the cause of the patient’s condition, hyperkalemic periodic paralysis, in a mutation of a gene that coded for a muscle cell sodium channel.^[2][3] This invoked a series of discoveries of mutant ion channel genes which constructed the framework for studying similar diseases which Ptacek calls “channelopathies.”^[4]

In 1999, Christopher Jones, a neurologist from University of Utah who specializes in sleep disorders, contacted Ptacek to characterize a family of early risers and find the genes associated with this phenotype.^[2] 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 (FASPS).^[5]

Research

Episodic diseases

Channelopathies

Ptacek began his research on episodic neurological diseases by cloning and identifying genes that were responsible for periodic paralysis and non-dystrophic myotonia.^[1] His research focused 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.^[6] He helped discover that hyperkalemic periodic paralysis, paramyotonia congenita, Andersen-Tawil syndrome, and other diseases are caused by mutations in voltage gated ion channels for sodium, calcium, chloride and potassium ions.^[6]

Andersen-Tawil Syndrome

His current research mainly focuses on identifying the genes involved with Andersen-Tawil syndrome (ATS). Ptacek'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.^[7] Thus far, Ptacek and his colleagues have identified six disease-causing mutations, five of which are dominant negative mutations that mask the wild-type allele.^[6] With his continued research on ATS, Ptacek has discovered and identified additional phenotypic diagnostic criteria for ATS using skeletal and dental findings.^[8]

Thyrotoxic periodic paralysis (TPP)

Ptacek, 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 channel. This protein channel, highly similar to Kir2.2, is transcriptionally regulated by the 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.^[9]

Human Sleep Behavior

Familial advanced sleep phase syndrome (FASPS)

In 1999, Ptacek was introduced to a family in Utah 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 later coined the term familial advanced sleep phase syndrome (FASPS).^[2] The disorder is characterized by around an four hour phase advance, causing individuals to sleep from approximately 7:30 pm to 4:30 am.

In 2001, Ptacek and his colleagues localized the autosomal dominant FASPS gene. They identified the point mutation from serine to glycine at amino acid site 662, in the casein kinase 1${\displaystyle \epsilon }$ binding region of the gene hPer2, causing hypophosphorylation and altering the circadian period in these affected individuals.^[10]

Ptacek, with his colleagues, have also found that a mutation in hPer2 is not the only gene that causes FASPS, and current research is exploring other sporadic cases of FASPS to identify new mutations that contribute to the syndrome.^[11]

Awards and Honors

Selected Publications

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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