The genetic aetiology of retinal degeneration in children in Finland – new founder mutations identified

Purpose To study the genetic aetiology and phenotypes of retinal degeneration (RD) in Finnish children born during 1993-2009. Methods Children with retinal degeneration (N = 68) were investigated during 2012-2014 with a targeted gene analysis or a next-generation sequencing (NGS) based gene panel. Also, a full clinical ophthalmological examination was performed. Results The cohort covered 44% (68/153) of the Finnish children with inherited RD born 1993-2009. X-linked retinoschisis, retinitis pigmentosa, Leber congenital amaurosis and cone-rod dystrophy were the most common clinical diagnoses in the study group. Pathogenic mutations were found in 17 retinal genes. The molecular genetic aetiology was identified in 77% of the patients (in 77% of the families) analysed by NGS method. Several founder mutations were detected including three novel founder mutations c.148delG in TULP1, c.2314C>R (p.Gln772Ter) in RPGRIP1 and c.533G>A (Trp178Ter) in TYR. We also confirmed the previous tentative finding of c.2944 + 1delG in GYCU2D being the most frequent cause of Leber congenital amaurosis (LCA) in Finland. Conclusions Globally, RD is genetically heterogeneous with over 260 disease genes reported so far. This was shown not to be the case in Finland, where the genetic aetiology of RD is caused by a small group of genes, due to several founder mutations that are enriched in the population. We found that X-chromosomal retinoschisis constitutes the major group in Finnish paediatric RD population and is almost exclusively caused by two founder mutations. Several other founder mutations were detected including three novel founder mutations. All in all, the genetic aetiology of 77% of families was identified which is higher than previously reported from other populations, likely due to the specific genomic constitution of the Finns.Peer reviewe

Rescue of cell surface expression and signaling of mutant follicle-stimulating hormone receptors

Mutations in G protein-coupled receptors (GPCRs) underlie numerous diseases. Many cause receptor misfolding and failure to reach the cell surface. Pharmacological chaperones are cell-permeant small molecules that engage nascent mutant GPCRs in the endoplasmic reticulum, stabilizing folding and "rescuing" cell surface expression. We previously demonstrated rescue of cell surface expression of luteinizing hormone receptor mutants by an allosteric agonist. Here we demonstrate that a similar approach can be employed to rescue mutant follicle-stimulating hormone receptors (FSHRs) with poor cell surface expression using a small-molecule FSHR agonist, CAN1404. Seventeen FSHR mutations described in patients with reproductive dysfunction were expressed in HEK 293T cells, and cell surface expression was determined by enzyme-linked immunosorbent assay of epitope-tagged FSHRs before/after treatment with CAN1404. Cell surface expression was severely reduced to ≤18% of wild-type (WT) for 11, modestly reduced to 66% to 84% of WT for 4, and not reduced for 2. Of the 11 with severely reduced cell surface expression, restoration to ≥57% of WT levels was achieved for 6 by treatment with 1 µM CAN1404 for 24 h, and a corresponding increase in FSH-induced signaling was observed for 4 of these, indicating restored functionality. Therefore, CAN1404 acts as a pharmacological chaperone and can rescue cell surface expression and function of certain mutant FSHRs with severely reduced cell surface expression. These findings aid in advancing the understanding of the effects of genetic mutations on GPCR function and provide a proof of therapeutic principle for FSHR pharmacological chaperones.https://academic.oup.com/endohj2022ImmunologyPhysiolog

A Study on Prevalance of Hypothyroidism in Patients with Extra Hepatic Biliary Lithiasis

AIM : To show the prevalence of clinical or subclinical hypothyroidism in patients with gallstones and common bile duct stones Back ground : Studies have shown an increased prevalence of previously diagnosed hypothyroidism in gallstone patient and a delayed emptying of the biliary tract in hypothyroidism, explained partly by the missing pro relaxing effect of thyroxine on the sphincter of oddi contractility. Other explanations include the known link between thyroid failure and disturbances of lipid metabolism that may consecutively lead to change of the composition of the bile and motility of biliary tract. PATIENT AND METHOD : An observational study was done in Institute of Surgery, Rajiv Gandhi Government General Hospital, Chennai between June 2014 to June 2015. For the 195 patients with diagnosed gallstone / CBD stone, full history and clinical examination was taken and laboratory blood test for T3, T4 and TSH was done. A control group of 100 patients of similar age and sex profile admitted in same time period for other illness were also evaluated for hypothyroidism. RESULTS : Out of 195 patients with gallstone 148 (76%) were females and 47 (24%) males. Thyroid disorder in form of hypothyroidism was found in 45 (23%), from this percentage 36 (24%) were females and from this 27 (18%) were subclinical and 9 (6%) were clinical hypothyroidism and males were 9 (19%) with all subclinical cases except one. This was compared with a control group of 100 patients, 80 (80%) were females and 20 (20%) males. Hypothyroidism was found in 9 (9%) patients, all female. CONCLUSION AND RECOMMENDATION : There is a significant association between hypothyroidism and gallstones / CBD stones in both genders. Gallstone and CBD stone patients, especially females should be checked for serum TSH, T3 and T4 because of high incidence of hypothyroidism among this group

Association of Cholelithiasis, Choledocholithiasis and Hypothyroidism

INTRODUCTION: Thyroid disorder is a prevalent condition among adult population; however, it is frequently over looked.. Hypothyroidism causes low bile flow and sphincter of Oddi dysfunction and hence promotes gall stone formation. This study was done to substantiate the need for evaluating the thyroid status in patients presenting with cholelithiasis/ choledocholithiasis. AIMS: To study the prevalence of hypothyroidism in patients presenting with CHOLELITHIASIS/ CHOLEDHOCOLITHIASIS.To assess if thyroid profile is indicated in patients with biliary lithiasis. MATERIALS AND METHODS: This is an observational and prospective study. Method of sampling was non-random, purposive. 68 patients with USG evidence of cholelithiasis/ choledocholilithiasis, were evaluated with basic investigations and additionally thyroid function test was performed. The operation procedure and related per operative factors were observed directly and recorded. RESULTS: The operation procedure and related per operative factors were observed directly and recorded in the data collection sheet instantly. Age of these selected patients ranged from 20- 70 yrs, with mean age being 47.14 yrs. 32% were male patients and 68% were female patients. The male to female ratio is 1: 2. Females were the predominant group. Thyroid function test was performed in all 68 patients out of which, 18 patients (26.4%) were found to have hypothyroidism and the rest i.e. 50 patients were euthyroid. Of these 18 patients only 2 were known hypothyroid, rest 16 patients were newly diagnosed hypothyroid patients .Of these 18 patients, 16 patients were females rest were males. 50-70 yrs were the predominant group. More than 70% of the patients with hypothyroidism belong to this group. CONCLUSION: Evaluation of thyroid profile should be a part of general workup in patients with both cholelithiasis and choledocholithiasis especially in females above the age of 40yrs and patient should be treated with appropriate thyroid medications

Myeloid cell expressed proprotein convertase FURIN attenuates inflammation

The proprotein convertase enzyme FURIN processes immature pro-proteins into functional end- products. FURIN is upregulated in activated immune cells and it regulates T-cell dependent peripheral tolerance and the Th1/Th2 balance. FURIN also promotes the infectivity of pathogens by activating bacterial toxins and by processing viral proteins. Here, we evaluated the role of FURIN in LysM+ myeloid cells in vivo. Mice with a conditional deletion of FURIN in their myeloid cells (LysMCre-fur(fl/fl)) were healthy and showed unchanged proportions of neutrophils and macrophages. Instead, LysMCre-fur(fl/fl) mice had elevated serum IL-1\u3b2 levels and reduced numbers of splenocytes. An LPS injection resulted in accelerated mortality, elevated serum proinflammatory cytokines and upregulated numbers of pro-inflammatory macrophages. A genome-wide gene expression analysis revealed the overexpression of several pro-inflammatory genes in resting FURIN-deficient macrophages. Moreover, FURIN inhibited Nos2 and promoted the expression of Arg1, which implies that FURIN regulates the M1/M2-type macrophage balance. FURIN was required for the normal production of the bioactive TGF-\u3b21 cytokine, but it inhibited the maturation of the inflammation-provoking TACE and Caspase-1 enzymes. In conclusion, FURIN has an anti-inflammatory function in LysM+ myeloid cells in vivo