HERITABLE DISORDERS BRANCH
Joan C. Marini, MD, PhD, Chief, June 1995 to September 30, 2003 Constantine Stratakis, MD, DSc, Acting Chief from October 1, 2003

 
Joan Marini's research program on osteogenesis imperfecta (OI) within the Heritable Disorders Branch (HDB) has focused on the effects of the bisphosphonate drugs in both children and mice with OI and on a collaborative study of an interesting subset of OI patients who have both OI and Ehlers-Danlos syndrome. Treatment of the Brtl mouse model for OI, previously generated by Marini's group, the Section on Connective Tissue Disorders, and of children with types III and IV OI resulted in increased bone density. However, biomechanical tests of murine femurs did not show improvement in the brittleness of the bone. For the OI/EDS cases, the laboratory defined a five-exon region of type I collagen in which mutations cause EDS symptoms by retention of the N-propeptide. As of October, 2003, this research was continued in the Bone and Extracellular Matrix Branch.   

Denny Porter's group, the Unit on Molecular Dysmorphology,studies children with disorders of cholesterol synthesis, including the Smith-Lemli-Opitz syndrome, and generates murine models for those disorders. The carrier frequency for SLOS in African Americans was found to be 0.73 percent, similar to the frequency in Caucasians, and phenotypic variants are being sought. The group has generated a new mouse model for defects in the enzymatic step immediately preceding the SLOS defect and identified a patient with the novel lathosterolosismalformation syndrome. Comparison of the lathosterolosis mouse with the SLOS mouse model will yield important insights into the hedgehog signaling pathway.
 
The investigations of Janice Chou's laboratory, the Section on Cellular Differentiation, have focused on glycogen storage disease and G6PT. A structure-function study of the G6PT used an adenoviral vector-mediated expression system and found that most codon mutations completely abolish microsomal G6P uptake activity while others partially inactivate uptake. Mutations have also been characterized within the signature motif shared by G6PT and a family of transporters of phosphorylated metabolites, showing that the motif is a functional element required for microsomal transport. Using its murine knockout for G6PT, the group has demonstrated that the neutropenia associated with the disorder is directly caused by the loss of G6PT activity.
 
The Section on Developmental Genetics, led by Anil Mukherjee, focuses on heritable autoimmune and neurodegenerative disorders and is engaged in a pilot study to determine if cystagon is an effective treatment for infantile neuronal ceroid lipofuscinosis (INCL). The group is using a mouse model of INCL to understand the molecular mechanisms of the disease. The researchers have recently demonstrated that uteroglobin is a repressor of PGD₂ receptor-mediated COX-2 gene expression and an inhibitor of prostaglandin F₂a receptor-mediated activation of NF-kappaB expression and that uteroglobin knock-out mice are predisposed to lung tumors when exposed to NNK commonly present in cigarette smoke.
 
Ida Owens's group, the Section on Genetic Disorders of Drug Metabolism, focuses on the molecular biology, regulation, and biochemistry of UDP-glucuronosyltransferase enzymes and has discovered that the isozymes require phosphorylation that is regulated through signaling. The section also has evidence that phospho-groups play an operational role in catalysis rather than causing the typical conformational change in protein structure. The bilirubin-metabolizing isozymes are segmentally distributed through the GI system and may play an important role in limiting GI absorption of polyphenols.