Homozygous mutation in CSF1R causes brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS).

Introduction: The CSF1R gene encodes the receptor for colony-stimulating factor-1, the macrophage, and monocyte-specific growth factor. Mutations in this gene cause hereditary diffuse leukoencephalopathy with spheroids (HDLS) with autosomal dominant inheritance and BANDDOS (Brain Abnormalities, Neurodegeneration, and Dysosteosclerosis) with autosomal recessive inheritance. Methods: Targeted gene sequencing was performed on the genomic DNA samples of the deceased patient and a fetus along with ten healthy members of his family to identify the disease-causing mutation. Bioinformatics tools were used to study the mutation effect on protein function and structure. To predict the effect of the mutation on the protein, various bioinformatics tools were applied. Results: A novel homozygous variant was identified in the gene CSF1R, c.2498C>T; p.T833M in exon 19, in the index patient and the fetus. Furthermore, some family members were heterozygous for this variant, while they had not any symptoms of the disease. In silico analysis indicated this variant has a detrimental effect on CSF1R. It is conserved among humans and other similar species. The variant is located within the functionally essential PTK domain of the receptor. However, no structural damage was introduced by this substitution. Conclusion: In conclusion, regarding the inheritance pattern in the family and clinical manifestations in the index patient, we propose that the mentioned variant in the CSF1R gene may cause BANDDOS.

A new report of autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID) with a homozygous pattern from Iran.

Autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID) is an autosomal dominant autoinflammatory disease characterized by episodic skin, musculoskeletal, ophthalmic and gastrointestinal tract symptoms. Here we report an 11-year-old girl with a history of repeated episodes of fever, myalgia, arthralgia, abdominal pain, and urticarial rash in the trunk and limbs. Chest and pelvic X-Ray, sacroiliac joints MRI, brain MRI and abdominal CT scan were normal. Anti-nuclear antibody, Rheumatoid factor, cryoglobulin, ANCA/PR3, p-ANCA/MPO, anti-smooth muscle antibody and anti-mitochondrial antibody were negative. Serology for cytomegalovirus, Epstein-Barr, hepatitis B, hepatitis C, and HIV viruses was negative. Serum immunoglobulins were in the normal range. Genetic analysis for familial Mediterranean fever syndrome was negative. Whole exome sequencing was carried out to identify the genetic cause of our patient. We identified a homozygous missense variant (c.579C > G, p. His193Gln) in exon 7 of the PLCG2 gene. Bioinformatic analysis and clinical symptoms suggests this variant to be pathogenic in the homozygous state for APLAID and thus probably acting in an autosomal recessive manner. Our bioinformatic analysis also showed this novel mutation to have detrimental effects on the 3D structure of the PLCG2 protein, which is well conserved among many other similar species.

Association of TNF-α -857 Polymorphism with Inflammatory Bowel Disease in a Group of Iranian Azeri Individuals.

BACKGROUND Inflammatory bowel disease (IBD) is a chronic, relapsing, inflammatory disorder of the gastrointestinal tract that includes two entities, Crohn's disease (CD) and ulcerative colitis (UC). As with other complex diseases, both genetic susceptibility and environmental factors play role in the pathogenesis of these diseases. The tumor necrosis factor α (TNF-α) gene is located in the IBD3 region on chromosome 6p21 which is a good functional candidate for involvement in susceptibility to IBD. In addition, the promoter region of TNF-α contains various polymorphisms that have shown a significant association with IBD. METHODS In this case control study we investigated the TNF-α -857 polymorphism in 109 patients (89 UC and 16 CD) who suffered from IBD and 100 healthy age, sex and ethnicity matched adults selected from the same population, as the control group. The polymorphism was checked by amplification refractory system (ARMS) and polymerase chain reaction (PCR). RESULTS Investigation of the association of TNF-α -857 gene promoter polymorphism with both types of IBD showed no significant difference in genotype and allele frequencies of this polymorphism between UC patients and controls. However, a possible association of TNF-α -857 polymorphism (p=0.03) was identified with CD. CONCLUSION TNF-α -857 polymorphism may have a role in the development of CD in the Iranian Azeri Turkish population.