AB1035 MAFB-VARIANTS IN MULTICENTRIC CARPOTARSAL OSTEOLYSIS WITH NEPHROPATHY DO NOT SEEM TO AFFECT SERUM C1Q CONCENTRATION

Abstract

Background Multicentric carpotarsal osteolysis syndrome (MCTO)-associated progressive nephropathy is an orphan disease associated with well-known structural kidney damage that usually requires kidney transplantation in adulthood. Although ACE-inhibitors could potentially slow down the progression of kidney dysfunction, other treatments would be welcome. Furthermore, a slight proteinuria reduction in a patient with MCTO treated with cyclosporine has been reported. MafB-deficient mice develop systemic lupus erythematous-like autoimmune disease by inhibited C1q production and efferocytosis. In the human, monoallelic mutations in MafB result in MCTO. Objectives To investigate whether C1q levels in patients with MCTO are reduced and might contribute to the development of renal disease. Methods In three individuals with clinical and radiographic signs of MCTO, the MAFB gene was sequenced. The serum C1q concentration was determined with a commercial laboratory kit. Results Three patients with MCTO were enrolled (table 1). Patient A presented recurrent urinary tract infections since 18 months of life for a third-degree vesicoureteral reflux. Despite correction surgery, he displayed proteinuria after one year, and kidney biopsy did not reveal significant lesions. After two years, he displayed bilateral tarsal malformations requiring orthopedic surgery. At the age of 6, a pathological fracture of the right wrist occurred, and local X-ray revealed osteolysis of carpal bones. - Because of a suspected juvenile idiopathic arthritis of the right wrist, patient B was treated with intra-articular steroid injection and subcutaneous methotrexate for one year without benefit. After one year, he developed proteinuria and kidney biopsy revealed focal segmental glomerular lesions with tubular fibrosis and renal vasa sub-intimal delamination. C3 and C4 positive mesangial deposits were also present. - Patient C was referred to us for suspected juvenile idiopathic arthritis of the right wrist. No inflammatory signs were present at the ultrasound examination. Sequencing of the MAFB gene revealed in all the patients a novel heterozygous mutation. Although specific variants have not been reported before, the nature and position of the variants associated with the clinical features of the patients strongly argued in favor of their pathogenic role. The serum C1q concentration was normal in all the patients. Conclusion C1q plasma levels in our patients were normal, suggesting that MCTO-associated genetic variants do not play a role in MafB-dependent regulation of complement component C1q production in humans. Further studies are necessary to exclude a role of complement system in the progressive nephropathy of patients with MCTO.