Tomohiro Udagawa1, Tohaku Jo2, Takeshi Yanagihara2, Akira Shimizu3, Jun Mitsui4, Shoji Tsuji4, Shinichi Morishita5, Reiko Onai1, Kenichiro Miura1, Shoichiro Kanda1, Yuko Kajiho1, Haruko Tsurumi1, Akira Oka1, Motoshi Hattori6, Yutaka Harita7. 1. Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. 2. Department of Pediatrics, Nippon Medical School, Tokyo, Japan. 3. Department of Analytic Human Pathology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan. 4. Department of Neurology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. 5. Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan. 6. Department of Pediatric Nephrology, Tokyo Women's Medical University, Sinjuku-ku, Tokyo, Japan. 7. Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. haritay-ped@h.u-tokyo.ac.jp.
Abstract
BACKGROUND: Steroid-resistant nephrotic syndrome (SRNS) is a genetically heterogeneous disorder for which more than 25 single-gene hereditary causes have been identified. METHODS: Whole exome sequencing was performed in a 3-year-old girl with SRNS. We analyzed the expression of Crb2 and slit diaphragm molecules in the patient's glomeruli, and compared it with that of controls or other nephrotic patients. RESULTS: Whole-exome analysis identified novel compound heterozygous mutations in exons 10 and 12 of CRB2 (p.Trp1086ArgfsX64 and p.Asn1184Thr, each from different parents; Asn1184 within extracellular 15th EGF repeat domain). Renal pathology showed focal segmental glomerulosclerosis with effaced podocyte foot processes in a small area, with significantly decreased Crb2 expression. Molecules critical for slit diaphragm were well-expressed in this patient's podocytes. Crb2 expression was not altered in the other patients with congenital nephrotic syndrome with NPHS1 mutations. CONCLUSIONS: These findings demonstrate that Crb2 abnormalities caused by these mutations are the mechanism of steroid-resistant NS. Although CRB2 mutations previously found in SRNS patients have been clustered within the extracellular tenth EGF-like domain of this protein, the present results expand the variation of CRB2 mutations that cause SRNS.
BACKGROUND:Steroid-resistant nephrotic syndrome (SRNS) is a genetically heterogeneous disorder for which more than 25 single-gene hereditary causes have been identified. METHODS: Whole exome sequencing was performed in a 3-year-old girl with SRNS. We analyzed the expression of Crb2 and slit diaphragm molecules in the patient's glomeruli, and compared it with that of controls or other nephroticpatients. RESULTS: Whole-exome analysis identified novel compound heterozygous mutations in exons 10 and 12 of CRB2 (p.Trp1086ArgfsX64 and p.Asn1184Thr, each from different parents; Asn1184 within extracellular 15th EGF repeat domain). Renal pathology showed focal segmental glomerulosclerosis with effaced podocyte foot processes in a small area, with significantly decreased Crb2 expression. Molecules critical for slit diaphragm were well-expressed in this patient's podocytes. Crb2 expression was not altered in the other patients with congenital nephrotic syndrome with NPHS1 mutations. CONCLUSIONS: These findings demonstrate that Crb2 abnormalities caused by these mutations are the mechanism of steroid-resistant NS. Although CRB2 mutations previously found in SRNS patients have been clustered within the extracellular tenth EGF-like domain of this protein, the present results expand the variation of CRB2 mutations that cause SRNS.
Authors: R Jaron; N Rosenfeld; F Zahdeh; S Carmi; L Beni-Adani; V Doviner; E Picard; R Segel; S Zeligson; L Carmel; P Renbaum; E Levy-Lahad Journal: Clin Genet Date: 2016-05-02 Impact factor: 4.438
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