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Background: The use of microsomal triglyceride transfer protein (MTP) inhibitors is limited to severe hyperlipidemias due to associated hepatosteatosis. Comprehensive knowledge about the structure-function of MTP might help design new molecules that avoid steatosis. Characterization of mutations in MTP causing abetalipoproteinemia (ABL) have revealed that the central α-helical and C-terminal β-sheet domains are important for protein disulfide isomerase (PDI) binding and lipid transfer activity. Our aim was to identify and characterize ABL mutations in the N-terminal region to understand the function of this domain. Methods and Results: We identified a novel missense mutation (D169V) in a 4-month old Turkish male with severe signs of ABL. To study the effect of this mutation on MTP function, we created mutants via site directed mutagenesis. Although D169V was expressed in the endoplasmic reticulum and interacted with apoB17, it was unable to bind PDI, transfer lipids, and support apoB secretion. Computational modeling suggested that D169 could form an internal salt bridge with K187 and K189. Mutagenesis of these lysines to leucines abolished PDI heterodimerization, lipid transfer, and apoB secretion, without affecting apoB binding. Further, mutants with preserved charges (D169E, K187R, K189R) rescued these activities. Conclusions: D169V is detrimental because it disrupts an internal salt bridge leading to loss of PDI binding and lipid transfer activities; however, it does not affect apoB-binding. We propose that future inhibitors should avoid this region of the N-terminal domain.

Microsomal triglyceride transfer protein (MTP) is critical for the assembly and secretion of apolipoprotein B (apoB)-containing lipoproteins. Mutations in the MTTP gene cause abetalipoproteinemia (ABL). Missense mutations in ABL have revealed that the central α-helical and C-terminal β-sheet domains are important for the lipid transfer activity of MTP and for the assembly and secretion of apoB-containing lipoproteins. The N-terminal domain, on the other hand, has mainly been implicated in apoB- and membrane-binding. Here, we describe a novel ABL missense mutation (D169V) in the N-terminal β-sheet of MTP. Although this mutant MTP (MTPD169V) is expressed and localized to the endoplasmic reticulum, it is unable to transfer triglycerides and phospholipids. Further, MTPD169V does not support the assembly and secretion of apoB-containing lipoproteins. Computational molecular modeling suggests that D169 could form an internal salt bridge with K187 and K189. Indeed, mutagenesis of these lysine residues to leucine abolishes triglyceride transfer and apoB secretion activities of MTP. Furthermore, conservative mutagenesis that preserves charges on these residues partially restores triglyceride transfer and apoB secretion activities of MTP. Therefore, D169 is probably involved in an internal salt bridge with K187 and K189. Disruption of this internal salt bridge in the N-terminal region affects the lipid transfer activity present in the C-terminal end of the MTP molecule. We speculate that this salt bridge, although away from the speculated lipid transfer site, might be important in providing structural integrity necessary for the lipid transfer activity of MTP.

The aims of this study were to evaluate bone mineral density (BMD) in patients with juvenile chronic arthritis (JCA), compare them with healthy controls, and assess the effects of disease activity and corticosteroid treatment on BMD. Twenty-eight patients diagnosed with JCA and 45 healthy controls were included in this study. Disease activity was determined by clinical and laboratory evaluation, Articular Disease Severity Score (ADSS), and the Juvenile Arthritis Functional Assessment Report (JAFAR). Bone mineral density of the lumbar spine was measured by dual energy X-ray absorptiometry (DEXA). Patients with JCA showed significant decreases in BMD compared with healthy controls. The JCA patients treated with corticosteroids showed significantly lower BMDs than the healthy control group. Age of the patients and age of onset were found to correlate with BMD. Our study showed that glucocorticoids were involved in the development of osteoporosis in JCA, with many other factors affecting bone mineralization. We could not demonstrate any relationship between BMD and disease activity, but the study data suggest that early onset disease is also an important factor in the development of osteoporosis in JCA.

We present a female infant with facial abnormalities such as bilateral cleft lip and palate, ectrodactyly and central diabetes insipidus. She had a history of recurrent hypernatremic attacks and she was treated successfully with oral desmopressin. As an alternative to the nasal route, long-term management was achieved using oral route and she had a favorable growth and development during infancy.

OBJECTIVES To investigate the value of nasal cytology in the diagnosis of sinusitis and follow-up of atopic and nonatopic children before and after treatment and to compare the nasal cytologic findings with the radiologic findings. DESIGN Open randomized investigation. SETTING Ministry of Health, Ankara Diskapi Children's Hospital. METHOD Fifty-five children with bronchial asthma and/or allergic rhinitis followed by the Allergy Department of the Ministry of Health, Ankara Diskapi Children's Education and Research Hospital and 35 control children were evaluated for the following parameters: symptoms and signs of sinusitis, total serum immunoglobulin E level and eosinophil count, skinprick tests to common allergens, paranasal sinus radiographs, and nasal cytology (by the Rhinoprobe [Synbiotics Inc. London] method and wax paper blow). MAIN OUTCOME MEASURES Nasal cytology, radiologic findings, and treatment. RESULTS There were no significant correlations between radiologic and cytologic findings in any of the groups (p > .05). In both atopic and nonatopic chronic sinusitis patients, the Rhinoprobe method had results similar to the radiologic findings, and there was a significant relationship (p < .05). CONCLUSIONS Nasal cytology is still a diagnostic tool in the follow-up and evaluation of chronic sinusitis in atopic children but should not be considered an adequate alternative to sinus radiography.