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Genetics
and Biology of HumanNervous System Disorders
Characterization of genes that cause normal variations and disorders
of the nervous system.
One area of particular interest has been in episodic
disorders of muscle, heart, and brain. In many cases, these episodic
phenomena result from
alterations in electrical signaling of cell membranes in these tissues.
Initially, by studying a complex group of clinical phenotypes called
the periodic paralyses and non-dystrophic myotonias, we began systematically
mapping and cloning genes responsible for these phenotypes. These have
turned out to be genes that encode ion channels with specificity for
sodium, calcium, chloride, and potassium ions. Once identified, it has
been possible for us and others to express wild-type and mutant ion channel
genes in heterologous expression systems to characterize functional consequences
of mutations in the function of these channels. This approach has been
very complimentary to site-directed mutagenesis studies that have been
done without attention to any particular human disease. These “experiments
of nature” focus our attention on discrete regions of the channels
and thus can be very informative for structure-function studies. Ongoing
work is focused on looking for epistatic interactions between these and
other genes, and modeling of the human diseases in other organisms such
as mice. The ability to study mutations in vivo will allow us to ask
questions that cannot be approached because of the difficulty in obtaining
human tissues.
An ion channel with a role in development.
Recently we have identified a gene that causes a rare disorder called
Andersen-Tawil syndrome (ATS). The gene accounting for a majority of
the families that we've identified is KCNJ2 . This gene encodes an inwardly
rectifying potassium channel (Kir2.1). Interestingly, ATS is clinically
recognized as a triad of periodic paralysis, cardiac arrhythmias, and
developmental features affecting the face and limbs. We have done extensive
work in characterizing the physiological consequences of these mutations
on Kir2.1 currents and also have identified mutations that affect co-assembly
and trafficking of these proteins. We've also generated transgenic mice
which will allow us to ask questions regarding the role this inwardly
rectifying potassium channel in development of cranio-facial and limb
structures.
In addition, we are continuing to search for genes causing other episodic
phenomena. In a number of cases (epilepsy, movement disorders) the genes
that we've identified are not ion channels and represent new windows
into understanding other aspects of these episodic phenomena outside
of being primary determinants of membrane excitability.
Human circadian rhythm genetics and biology.
We became interested in human circadian rhythm genetics upon identifying
and characterizing the first human family with a Mendelian variant in
their sleep schedule (in collaboration with the laboratory of Ying-Hui
Fu). We've gone on to show that these individuals have a familial form
of advanced sleep phase syndrome (FASPS). They are normal and healthy
but are extreme morning larks. These individuals have a short circadian
period that leads them to wake up earlier each day. They ultimately reach
an equilibrium where they're waking up so early and going to sleep early
enough that they get a strong light impulse to reset their clock for
the next day. We've now collected over fifty families with FASPS and
are characterizing candidate circadian rhythm genes for variants that
cause this phenotype and studying the biochemistry and cell biology of
the genetic variants that we're identifying. Furthermore, families that
don't have genetic variants in any of the known or predicted candidate
genes will provide opportunities to identify novel genetic contributions
to human circadian rhythmicity.
Selected Publications:
Bendahhou S, Cummins T, Kula R, Fu Y-H, Ptacek LJ. Impairment of slow
inactivation as a common mechanism for hyperkalemic periodic paralysis
in DIIS4-S5. Neurology 2002, 58:1266 72.
Tristani-Firouzi M, Jensen JL, Donaldson MR, Sansone V, Meola G, Hahn
A, Bendahhou S, Kwiecinski H, Fidzianska A, Plaster N, Fu Y-H, Ptacek
LJ, Tawil R. Functional and clinical characterization of KCNJ2 mutations
associated with LQT7 (Andersen’s Syndrome) J Clin Investigation
2002 Aug 1;110(3):381-388.
Nakayama J, Fu Y-H, Clark AM, Satoko N, Hamano K, Iwasaki N, Matsui A,
Arinami T, Ptacek LJ. A nonsense mutation of the MASS1 gene in a family
with febrile and afebrile seizures. Annals of Neurology 2002, 52:654-657.
Donaldson MR, Jensen JL, Tristani-Firouzi M, Tawil R, Bendahhou S, Suarez
WA, Cobo AM, Poza JJ, Behr E, Wagstaff J, Szepetowski P, Pereira S, Mozaffar
T, Escolar DM, Fu H-Y, Ptacek LJ. PIP2 binding residues of Kir2.1 are
common targets of mutations causing Andersen syndrome. Neurology 2003
Jun 10;60(11):1811-6.
Bendahou S, Donaldson MR, Plaster NM, Tristani-Firouzi M, Fu Y-H, Ptacek
LJ. Defective potassium channel Kir2.1 trafficking underlies Andersen-Tawil
syndrome. J Biol Chem, 2003;278(51):51779-85.
Contact Information:
Email: ptacek@itsa.ucsf.edu
Phone: 415/502-5614
Address: Box 2922, MB Bldg 19 B, 548F
The University of California, San Francisco, CA 94143, (415) 476-9000
Copyright 2003, The Regents of the University of California.
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