Constantine Stratakis, MD, DSc, Chief

During 2006, the Heritable Disorders Branch (HDB) continued its important work in the field of human molecular genetics.

The Section on Molecular Genetics of Heritable Human Disorders, headed by Janice Chou, studies glycogen storage disease type I (GSD-I). GSD-I is caused by deficiencies in the glucose-6-phosphatase-alpha (G6Pase-alpha) complex, which consists of a glucose-6-phosphate transporter (G6PT) and a G6Pase-alpha catalytic unit. Deficiencies in G6Pase-alpha cause GSD-Ia while deficiencies in G6PT cause GSD-Ib, both producing symptoms of disturbed glucose homeostasis; GSD-Ib patients also present with myeloid dysfunctions. Chou showed that myeloid dysfunctions in GSD-Ib are intrinsically linked to G6PT deficiency in bone marrow and neutrophils. Using G6Pase-alpha-/- mice, her group showed that adeno-associated virus-mediated gene therapy corrects metabolic abnormalities in GSD-Ia. Likewise, the G6PT-/- mice receiving adenoviral vector-mediated gene transfer exhibit improved metabolic and myeloid functions. This effective use of gene therapy to correct murine GSD-I holds promise for the future of gene therapy in humans.

The Section on Developmental Genetics, headed by Anil Mukherjee, conducts both laboratory and clinical investigations to understand molecular mechanism(s) of heritable childhood neurodegenerative diseases and inflammatory/autoimmune disorders. Investigations focus primarily on two genes: those encoding palmitoyl-protein thioesterase-1, mutation of which is the genetic basis of infantile Batten disease (IBD), and uteroglobin, deficiency in which leads to IgA nephropathy, allergic airway inflammation, and, in mice, tumor susceptibility. A major achievement during 2006 was the discovery that neuronal death in IBD is caused by endoplasmic reticulum stress-mediated activation of the unfolded protein response and apoptosis. The laboratory is now conducting a clinical trial to determine if a combined regimen of Cystagon™ and N-acetylcysteine (Mucomyst®) is beneficial for patients with infantile Batten disease.

The Section on Genetic Disorders of Drug Metabolism, headed by Ida Owens, studies regulation of UDP-glucuronosyltransferase (UGT) isozymes, focusing on understanding how UGT detoxifies innumerable endogenous chemical toxins as well as those encountered in our diet and environment. One of the group's recent findings was that UGTs require regulated phosphorylation and that their transient downregulation disrupts glucuronidation, leading to marked increases in uptake and efficacy of the widely used immunosuppressant mycophenolic acid. In addition, the Section discovered that UGT2B7, which detoxifies endogenous genotoxic catechol-estrogens, requires tyrosine phosphorylation. Importantly, UGT2B7 activity in normal and tumor breast tissue was associated with tyrosine phosphorylation and an active tyrosine kinase, indicating that phosphotyrosine(s) in 2B7 supports metabolism of genotoxic estrogen metabolites in breast tissue.

The Section on Molecular Dysmorphology, led by Forbes Porter, studies a group of human and mouse malformation syndromes attributable to inborn errors of cholesterol synthesis. The most common of these disorders is Smith-Lemli-Opitz syndrome (SLOS). The group studies both basic science and clinical aspects of the disorder. A major goal is to develop therapeutic interventions for SLOS. This past year the group published a paper demonstrating that simvastatin therapy was efficacious in an SLOS mouse model developed by the laboratory. The paper also reported that the laboratory has almost completed enrollment for a therapeutic trial designed to study the safety and efficacy of simvastatin therapy in SLOS children.