Research Interests

Drs. Jonathan and Christine Seidman have elucidated genetic causes of human disorders affecting calcium homeostasis (familial hypocalciuric hypercalcemia, neonatal severe hypoparathyroidism), hearing (sensorineural deafness, Bjornstad syndrome), tooth patterning and most importantly heart disease (cardiomyopathy, congenital malformations). The Seidman's discoveries include demonstration that cardiac myosin heavy chains, alpha-tropomysin, cardiac troponin T and cardiac myosin binding protein-C mutations cause hypertrophic cardiomyopathy,therein establishing a heretofore "idiopathic" condition as a contractile machinery disease. Their work has also uncovered the genetic basis for dilated cardiomyopathy and includes definition of mutations at distinct sites in contractile protein genes, and in titin, phospholamban and lamin A/C, and EYA4. Their findings improve diagnosis and through genotype/phenotype relationships provide prognostic information and aid sudden death risk stratification. The Seidmans also discovered the first genetic cause of congenital heart malformations, defining mutant transcription factor genes (TBX5, NKX2-5) in Holt-Oram syndrome and isolated heart malformations. The laboratory has also engineered many of these human mutations into mouse genomes and delineated biophysical properties of mutant sarcomeres and biochemical consequences of phospholamban and TBX5 defects. These investigations of cellular responses have identified critical roles for altered calcium homeostasis in cardiomyopathy, therein linking pathogenic mechanisms in inherited and acquired heart failure, work that provides a framework for design of rational therapies. Investigations of congenital heart disease models have reshaped classical paradigms from embryologic lineage to transcriptional regulation, work that that also indicates critical transcription factor levels for normal heart development.

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Primary Section

Section 42: Medical Physiology and Metabolism

Secondary Section

Section 26: Genetics