Browsing by Subject "http://www.yso.fi/onto/mesh/D001842"

Recently, mutations in the SGMS2 gene were shown to result in a rare disease known as osteoporosis with calvarial doughnut lesions. Affected patients present with severe, early-onset osteoporosis or skeletal dysplasia depending on the underlying mutation. In addition to the skeletal manifestations, patients also exhibit neurological symptoms, most commonly transient, spontaneously remitting, and recurring cranial nerve palsies. Similar neurological characteristics have previously been described in another rare condition known as Melkersson-Rosenthal syndrome (MRS). The objectives of this thesis were to provide a comprehensive review of literature on the role of sphingomyelin (SM) metabolism in the skeletal and central nervous systems and characterize the nature and prevalence of SGMS2 variants in cohorts of 14 Finnish MRS patients and 47 Finnish primary osteoporosis patients. The literature review explores the currently available data on SM metabolism in basic and clinical research. In bone, SM is suggested to hold a key role as a source of inorganic phosphate needed during mineralization and several studies have shown that aberrant SM metabolism leads to defective bone mineralization. In the central nervous system, SM metabolism has been shown to be altered in various pathologies, though the underlying pathophysiological mechanisms and their significance remain elusive. Genetic analyses of the cohorts were performed by extracting DNA from the patients’ whole blood, amplifying the coding and noncoding regions of the SGMS2 gene with PCR and using capillary sequencing to read the genetic code. Altogether 13 discrete single nucleotide variants were found, of which one was a missense variant present in two patients. The variant is relatively rare, has a high CADD score and is predicted probably damaging by computational software. The medical records of the two patients revealed nothing significantly deviating from the cohort norm. This thesis establishes that SGMS2 variants are not a common cause of primary osteoporosis or MRS in these two cohorts of Finnish patients. The significance of the identified missense variant warrants further studies.