Crystal structure and functional mapping of human ASMT,the last enzyme of the melatonin synthesis pathway

Abstract: Melatonin is a synchronizer of many physiological processes. Abnormal melatonin signaling is associated with human disorders related to sleep, metabolism, and neurodevelopment. Here, we present the X‐ray crystal structure of human N‐acetyl serotonin methyltransferase (ASMT), the last enzyme of the melatonin biosynthesis pathway. The polypeptide chain of ASMT consists of a C‐terminal domain, which is typical of other SAM‐dependent O‐methyltransferases, and an N‐terminal domain, which intertwines several helices with another monomer to form the physiologically active dimer. Using radioenzymology, we analyzed 20 nonsynonymous variants identified through the 1000 genomes project and in patients with neuropsychiatric disorders. We found that the majority of these mutations reduced or abolished ASMT activity including one relatively frequent polymorphism in the Han Chinese population (N17K, rs17149149). Overall, we estimate that the allelic frequency of ASMT deleterious mutations ranges from 0.66% in Europe to 2.97% in Asia. Mapping of the variants on to the 3‐dimensional structure clarifies why some are harmful and provides a structural basis for understanding melatonin deficiency in humans.     

Physiological effects of anterior repositioning splint on temporomandibular joint disc displacement: a quantitative analysis

Anterior repositioning splints (ARS) are used primarily for the management of temporomandibular joint (TMJ) anterior disc displacement with reduction (ADDwR). However, the exact physiological effects of ARS are still unclear. This study investigated the short and long‐term effects of ARS on disc and condyle angles/positions by metric analysis. Twenty‐two subjects diagnosed with ADDwR were recruited. Maxillary full‐coverage ARS were fabricated, and MRI of TMJs was obtained before splint treatment, immediate post‐insertion and 6 months after splint treatment. Disc–condyle relationship was determined by disc–condyle angle measurement. Disc and condyle positions were described as X‐Y coordinates with the summit of glenoid fossa as the origin of the coordinates. Thirty‐two TMJs were classified as ADDwR and 12 were normal. Upon ARS insertion, all TMJs with ADDwR got normal disc–condyle relationships. The condyles moved significantly forward and downward, while the discs moved significantly backward and upward. MRI at 6 months after treatment (without ARS insertion) indicated that only 40·6% (13/32) of the joints were maintained in the normal disc–condyle relationship. The majority of condyles returned to their pre‐treatment positions, while the discs generally moved anteriorly again. The use of ARS resulted in forward and downward condyle movement, and a concurrent backward movement of the disc resulting in ideal spatial disc–condyle relationship. The stability of this relationship, however, could not be maintained in the majority of TMJs upon ARS removal. Findings explain the good short‐term clinical outcomes with ARS and their relatively lower efficacy in the long term.     

A study of the SCN5A gene in a cohort of 76 patients with Brugada syndrome

We aim to study the SCN5A gene in a cohort of Brugada syndrome (BS) patients and evaluate the genotype–phenotype correlation. BS is caused by mutations in up to 10 different genes, SCN5A being the most frequently involved. Large genomic rearrangements in SCN5A have been associated with conduction disease, but its prevalence in BS is unknown. Seventy‐six non‐related patients with BS were studied. Clinical characteristics and family risk profile were recorded. Direct sequencing and multiplex ligation‐dependent probe amplification (MLPA) of the SCN5A gene for identification of mutations and larger rearrangements were performed, respectively. Eight patients (10.5%) had point mutations (R27H, E901K, G1743R (detected in three families), V728I, N1443S and E1152X). Patients with mutations had a trend toward a higher proportion of spontaneous type I Brugada electrocardiogram (ECG) (87.5% vs 52.9%, p = 0.06) and had evidence of familial disease (62.5%, vs 23.5%, p = 0.03). The symptoms and risk profile of the carriers were not different from wild‐type probands. There were non‐significant differences in the prevalence of type I ECG, syncope and history of arrhythmia in carriers of selected polymorphisms. None of the patients had any deletion/duplication in the SCN5A gene. In conclusion, 10.5% of our patients had mutations in the SCN5A gene. Patients with mutations seemed to have more spontaneous type I ECG, but no differences in syncope or arrhythmic events compared with patients without mutations. Larger studies are needed to evaluate the role of polymorphisms in the SCN5A in the expression of the phenotype and prognosis. Large rearrangements were not identified in the SCN5A gene using the MLPA technique.