Constantine Stratakis, MD, DSc, Acting Chief
The Heritable Disorders Branch (HDB) conducts clinical and molecular investigations of human genetic disorders.
The Section on Developmental Genetics, headed by Anil Mukherjee, conducts both basic and clinical investigations to understand molecular mechanisms of heritable neurodegenerative and inflammatory/autoimmune disorders in order to develop novel therapeutic approaches. Investigations focus primarily on two genes: uteroglobin (UG), also known as Clara cell 10kDa (CC10) protein, and palmitoyl-protein thioesterase-1 (PPT-1). The Section has reported on a clinical phenotype of UG-knockout mice and has been working on PPT1; mutations of this gene cause infantile neuronal ceroid lipofuscinosis (INCL), a heritable, uniformly fatal neurodegenerative disease of childhood. A clinical protocol is studying the effectiveness of the nucleophilic drug Cystagon™ as a therapy for INCL, and the Section is continuing efforts to understand the pathogenesis of INCL by using a PPT-knockout mouse model.
The Section on Molecular Genetics of Heritable Human Disorders, headed by Janice Chou, studies the glycogen storage diseases GSD-Ia and GSD-Ib, which are caused by deficiencies in G6Pase-alpha and the glucose-6-phosphate transporter (G6PT), respectively. The group generated a G6PT knockout mouse that mimics all known defects of the human disorder and used the model to investigate the pathogenesis of GSD-Ib. The Section continues its efforts to develop a somatic gene therapy for GSDIa. In particular, the Section infused G6Pase-alpha knockout mice with recombinant AAV1-mG6Pase-alpha, which led to sustained G6Pase-alpha expression in both the liver and kidney and corrected the murine disorder for 12 months. The group also identified G6Pase-beta, a ubiquitously expressed G6P hydrolase that couples functionally with G6PT to form an active G6Pase complex. The hydrolase is highly expressed in muscle, suggesting that muscle may have a previously unrecognized role in interprandial glucose homeostasis.
The Section on Genetic Disorders of Drug Metabolism, headed by Ida Owens, studies the regulation of UDP-glucuronosyltransferase (UGT, transferase) genes that encode enzymes that form the primary system for detoxifying potentially noxious chemicals taken into the body. In one of the year’s major findings, the Section reported that the condiment curcumin can enhance the action of the promising immunosuppressant mycophenolic acid (MPA), which is widely prescribed for renal transplant patients and autoimmune diseases. Given the serious side effects associated with high MPA dosage requirements due to extensive glucuronidation, the finding that oral curcumin pretreatment of antigen-treated mice can cause substantial enhancement of MPA immunosuppression of cytotoxic T-lymphocyte proliferation holds therapeutic promise.
The Unit on Molecular Dysmorphology, headed by Denny Porter, focuses on the pathophysiological processes that underlie the malformations and clinical problems in Smith-Lemli-Opitz syndrome (SLOS), a multiple malformation/mental retardation syndrome attributable to an inborn error of cholesterol biosynthesis. The group has developed a viable mouse model of SLOS for use in investigating various therapeutic interventions, such as simvastatin therapy, to improve the SLOS sterol abnormality in both peripheral tissues and the central nervous system. To test the potential for therapeutic intervention, the group has also initiated a clinical protocol to study the safety and efficacy of simvastatin therapy in SLOS patients.