RABENOSYN separation-of-function mutations uncouple endosomal recycling from lysosomal degradation, causing a distinct Mendelian disorder.

Rabenosyn (RBSN) is a conserved endosomal protein necessary for regulating internalized cargo. Here, we present clinical, genetic, cellular and biochemical evidence that two distinct RBSN missense variants are responsible for a novel Mendelian disorder consisting of progressive muscle weakness, facial dysmorphisms, ophthalmoplegia and intellectual disability. Using exome sequencing, we identified recessively acting germline alleles p.Arg180Gly and p.Gly183Arg, which are both situated in the FYVE domain of RBSN. We find that these variants abrogate binding to its cognate substrate phosphatidylinositol 3-phosphate (PI3P) and thus prevent its translocation to early endosomes. Although the endosomal recycling pathway was unaltered, mutant p.Gly183Arg patient fibroblasts show accumulation of cargo tagged for lysosomal degradation. Our results suggest that these variants are separation-of-function alleles, which cause a delay in endosomal maturation without affecting cargo recycling. We conclude that distinct germline mutations in RBSN cause non-overlapping phenotypes with specific and discrete endolysosomal cellular defects.

Intellectual disability, muscle weakness and characteristic face in three siblings: A newly described recessive syndrome mapping to 3p24.3-p25.3.

We report on a sister and two brothers born to healthy Iranian parents with mild intellectual disability, progressive muscle weakness, and characteristic facies. including highly arched eyebrows, down-slanting palpebral fissures, prominent nasal bridge, prominent nose, columella extending below alae nasi, narrow mouth, narrow palate, and dental caries, and in one of them an inability to abduct the left eye. Electrophysiological studies showed signs of myopathy, and muscle biopsies demonstrated only nonspecific signs. Brain MRIs in two of the sibs showed leukencephalopathy with delayed myelination, frontal and parietal hyperintensities, and hippocampal atrophy in one. We have been unable to find a description of this association of features in literature. Based on the occurrence in siblings, no significant difference in phenotype between the brothers and sister, absence of manifestations in parents, and a likely consanguinity between parents we performed a homozygosity mapping. A single identical-by-descent bloc encompassing 57 genes located at 3p24.3-p25.3 was found to segregate within the family with this phenotype. © 2015 Wiley Periodicals, Inc.

Food allergy among Iranian children with inflammatory bowel disease: A preliminary report.

BACKGROUND: Evidence has shown a link between allergic disease and inflammatory bowel diseases (IBDs). We investigated food allergy in Iranian pediatric IBD patients. MATERIALS AND METHODS: A cross-sectional study was conducted on a consecutive sample of children with newly diagnosed IBD referring to Mofid Children's University Hospital in Tehran (Iran) between November 2013 and March 2015. Data on age, gender, history of cow's milk allergy (CMA), IBD type, routine laboratory tests, and colonoscopic and histopathological findings were gathered. Food allergy was assessed with the skin prick test (SPT). RESULTS: A total of 28 patients including 19 ulcerative colitis (UC), 7 Cronh's disease (CD), and two with unclassified colitis with a mean age of 8.3 ± 4.4 years. (57.1% females, 42.9% were studied. History of CMA was present in eight patients (28.6%). Seventeen patients (60.7%) had at least one food allergy (68.4% of UC vs. 42.9% of CD, P = 0.230). Ten patients (35.7%) had multiple food allergies (36.8% of UC vs. 42.9% of CD, P > 0.999). Common allergic foods were cow's milk (28.6%), beef, seafood, albumen, wheat, and walnuts (each 10.7%), and peanuts and chestnuts (each 7.1%). The SPT showed CMA in 68.4% (8/17) of UC but none of the CD patients (P = 0.077). CONCLUSION: Food allergy is frequent in Iranian pediatric IBD patients with CMA being the most common observed allergy. The CMA seems to be more frequent in UC than in CD patients.