Functional characterization of novel mutations in GNPAT and AGPS, causing rhizomelic chondrodysplasia punctata (RCDP) types 2 and 3.

Rhizomelic chondrodysplasia punctata (RCDP) is a disorder of peroxisome metabolism resulting from a deficiency of plasmalogens, a specialized class of membrane phospholipids. Classically, patients have a skeletal dysplasia and profound mental retardation, although milder phenotypes are increasingly being identified. It is commonly caused by defects in the peroxisome transporter, PEX7 (RCDP1), and less frequently due to defects in the peroxisomal enzymes required to initiate plasmalogen synthesis, GNPAT (RCDP2) and AGPS (RCDP3). PEX7 transports AGPS into the peroxisome, where AGPS and GNPAT partner on the luminal membrane surface. The presence of AGPS is thought to be required for GNPAT activity. We present six additional probands with RCDP2 and RCDP3, and the novel mutations identified in them. Using cell lines from these and previously reported patients, we compared the amounts of both AGPS and GNPAT proteins present for the first time. We used protein modeling to predict the structural consequences of AGPS mutations and transcript analysis to predict consequences of GNPAT mutations, and show that milder RCDP phenotypes are likely to be associated with residual protein function. In addition, we propose that full GNPAT activity depends not only on the presence of AGPS, but also on the integrity of substrate channeling from GNPAT to AGPS.

Understanding and managing dental caries: a medical approach.

This article has taken a medical approach toward the understanding and managing of dental caries. Caries has been defined as a point in a person's life when there is an imbalance between protective and pathologic factors such that the process of demineralization of tooth structure by acid from bacteria in the tooth biofilm exceeds the patient's ability to remineralized tooth structure. The patient diagnosed with caries is out of balance. Caries is a diagnosis of a person. People have caries, teeth have lesions. Caries lesion detection, classification, and analysis are done at the level of the tooth surface. Caries is a process in time. Today we establish a diagnosis. For the future we establish a prediction. Patients can be diagnosed as caries active, caries balanced, or caries undetermined. For an improved treatment plan, future risk and prognosis assessments are accomplished by classifying all patients as either low, moderate, or high risk. A combination of diagnosis and risk or prognosis assessment leads to five treatment groups, each with an appropriate protocol for managing the disease process. The five protocols follow from the use of the four-step medical model for caries management. In the end, there are two treatment plans for these patients: a restorative therapy plan that treats the holes and a disease management plan that treats the disease. Surgical treatment does not manage the disease. Today we are managing tooth decay with medicine instead of a drill.