Biography
Steve A. N. Goldstein is Professor and Chairman of Pediatrics at The University of Chicago. He received his B.A. and M.A. in Biochemistry from Brandeis University (1978), his M.D. and Ph.D. from Harvard University (1986), his training in pediatric medicine and cardiology at Children's Hospital, Boston (1986-1993) and his training in ion channel biophysics with Christopher Miller (Brandeis University, 1989-1993). He was recipient of the E. Mead Johnson Award (2001) for his work on ion channel biophysics and cardiovascular medicine, and he was formerly Professor of Pediatrics and Cellular and Molecular Physiology, Chief of the Section of Developmental Biology and Biophysics and member of the Boyer Center of Molecular Medicine at Yale University.
Abstract
Cardiac Ion Channel Mutations in Sudden Childhood Death
Over the past 6 years, as genes for ion channels have been identified, the molecular mechanisms underlying normal cardiac function and sudden life-threatening diseases of the heart have become increasingly clear. Ion channels control the electrical activity of muscles and nerves. Dysfunction of ion channels leads to dangerous cardiac rhythms and may produce Sudden Infant Death Syndrome (SIDS). In some children, inherited mutations in ion channels cause disease directly; in others, gene variations lead to an unstable situation, a genetic predisposition, where a secondary challenge such as drug therapy incites a disorder. This proposal seeks to understand, diagnosis and prevent (a) inherited pediatric arrhythmia; (b) drug-induced pediatric arrhythmia; and, (c) SIDS, through pursuit of four Specific Aims:
- To identify children with these disorders.
- To evaluate ion channel genes in these children (and their relatives) for mutations and polymorphisms and assess the clinical significance (risk) of specific genetic variants.
- To study how genetic variation alters ion channel function to cause (or predispose to) disease.
- To develop improved methods to identify genetic variants associated with ion channel disease.
This proposal is feasible because our team cares for the majority of children in Connecticut with abnormal ECG findings, syncope/near syncope, palpitations, aborted sudden cardiac demise, seizures and many treated with arrhythmia-associated medications; moreover, all cases of SIDS in the State are now referred to the Goldstein laboratory for genetic study, and a collaboration with the NIH Pediatric Pharmacology Research Network (NICH-PPRU) is being designed. The proposal is timely and practical because the tools we need to proceed are now available. Thus, we have recently used these approaches to link both rare mutations and common polymorphisms in ion channel genes to inherited LQTS, drug-induced arrhythmia and periodic paralysis in adults and, thereby, elucidated some of the changes in ion channel physiology that lead to disease. Potential benefits of the proposal include the knowledge to avoid drug-induced arrhythmia (through pre-prescription genotyping), genotype-based risk assessment for sudden childhood deaths, interventions based on pathophysiology, and development of genetic tests for inherited and acquired pediatric arrhythmia (a real need as children are often quite difficult to diagnose). Through proven approaches and forays in new directions we seek to improve child health and train a remarkable group of students, fellows and junior faculty in bench-to-bedside research.