Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms

Mutations in the melanocortin-4 receptor gene (MC4R) represent the commonest monogenic cause of human obesity. However, information regarding the precise effects of such mutations on receptor function is very limited. We examined the functional properties of 12 different mutations in human MC4R that result in severe, familial, early-onset obesity. Of the nine missense mutants studied, four were completely unable to generate cAMP in response to ligand and five were partially impaired. Four showed evidence of impaired cell surface expression and six of reduced binding affinity for ligand. One mutation in the C-terminal tail, I316S, showed reduced affinity for alpha-MSH but retained normal affinity for the antagonist AgRP. None of the mutations inhibited signaling through co-transfected wild-type receptors. Thus, in the most comprehensive study to date of the functional properties of naturally occurring MC4R mutations we have (1) established that defective expression on the cell surface is a common mechanism impairing receptor function, (2) identified mutations which specifically affect ligand binding affinity thus aiding the definition of receptor structure-function relationships, (3) provided evidence against the notion that these receptor mutants act as dominant-negatives, and (4) identified a potentially novel molecular mechanism of receptor dysfunction whereby a mutation alters the relative affinities of a receptor for its natural agonist versus antagonist.     

A de novo mutation affecting human TrkB associated with severe obesity and developmental delay

An 8-year-old male with a complex developmental syndrome and severe obesity was heterozygous for a de novo missense mutation resulting in a Y722C substitution in the neurotrophin receptor TrkB. This mutation markedly impaired receptor autophosphorylation and signaling to MAP kinase. Mutation of NTRK2, which encodes TrkB, seems to result in a unique human syndrome of hyperphagic obesity. The associated impairment in memory, learning and nociception seen in the proband reflects the crucial role of TrkB in the human nervous system.     

Maffucci syndrome: Case report and review of diagnostic signs of the rare disease

Maffucci syndrome is a non-hereditary congenital condition that affects the skin and skeleton. Enchondromas (benign cartilage enlargements), bone abnormalities, and venous anomalies (hemangiomas) are all symptoms. Enchondromas occur as a result of mesodermal dysplasia and have the potential to become cancerous. They are most commonly found on the phalanges and long bones. Venous abnormalities commonly manifest themselves as soft lumps or tumors on the distal extremities. A 19-year-old boy presented with swellings on his fingers and left foot since the age of 5, along with a few bluish soft tissue swellings on his left heel. Multiple expansile lytic lesions and soft tissue swellings with phleboliths were seen on X-ray. Histology confirmed the diagnosis of hemangiomas and enchondromas. Soft tissue swellings were found to have hyper echoic areas, as well as modest marginal blood flow on Doppler, which could indicate hemangiomas. Maffucci syndrome was identified, and treatment with a multidisciplinary approach was initiated. Maffucci syndrome is a rare genetic illness reported in the literature less than 200 times. The enchondromas and hemangiomas have a strong link to malignant changes, with chondrosarcomas accounting for 30% of the associated malignancies. On X-ray, enchondromas are easily identified as osteolytic lesions with cortex thinning and endosteal scalloping while color Doppler ultrasound detects the presence of hemangiomas. Phleboliths are easily identified as small calcifications on X-rays. Radiographic examinations should be considered in patients presenting with bone or soft tissue swellings for an early diagnosis of Maffucci syndrome.     

Association between epstein barr virus and tongue squamous cell carcinoma in iranian patients

Detection of Epstein-Barr virus in oral squamous cell carcinoma suggests its involvement in the carcinogenesis of oral cavity. But, there are few studies on the incidence of EBV genome in squamous cell carcinomas at specific locations in the oral cavity like tongue and with different tumor progression. In this study the presence of EBV genome in tongue Squamous Cell Carcinoma (TSCC) in Iranian patients were investigated. Accordingly, a total of 94 cases with TSCC were firstly analyzed for the presence of viral genome through Nested PCR. Patients were divided into different groups based on their gender and the size, nodal involvement, grade and stage of their tumor. Results showed the presence of EBV genome in 72.3% of TSCCs with no significant difference between two genders, although slightly higher in females. Interestingly, PCR products of EBV genome showed a statistically significant higher distribution in TSCCs at IVa stage (p = 0.04), while a considerable low involvement of EBV genome was seen in T1-sized tumors. The result of this study further emphasizes the role of EBV in oral SCCs – mainly at tongue. This is the first investigation to clarify the association between EBV genome and different tumor size and stage in TSCCs; however, more studies in different regions and larger populations should be performed to be able to draw a firmed conclusion.     

Mutation analysis and immunopathological studies of PFN1 in familial and sporadic amyotrophic lateral sclerosis

Mutations in PFN1, a gene encoding the actin monomer-binding protein profilin 1, were recently reported in 1% to 2% of familial amyotrophic lateral sclerosis (ALS) patients. In vitro functional studies suggested that PFN1 mutations lead to ubiquitin-positive inclusions and impairment of cytoskeletal pathways. In the present study, mutation analysis of PFN1 was performed in an Australian cohort of 110 ALS families and 715 sporadic ALS patients. No PFN1 mutations were identified in familial ALS patients. Two rare non-synonymous variants (E117D and E117G) were found in sporadic ALS patients at similar incidences to that reported in public SNP databases. Immunostaining of PFN1 in sporadic ALS and familial ALS patients, including those with mutations in SOD1, FUS, UBQLN2 and C9ORF72, found no PFN1-positive inclusions in spinal motor neurons. Our data suggest that PFN1 mutations and pathology are not common in an Australian ALS cohort of predominantly European ancestry.