title: A human integrin-α3 mutation confers major renal developmental defects.
abstract: The development of the mammalian kidney is a highly complex process dependent upon the interplay of various cell types, secreted morphogens, and the extra-cellular matrix (ECM). Although integrins are the most important receptors for ECM proteins and are ubiquitously expressed during kidney development, mice lacking expression of integrin α3 (Itga3) do not demonstrate a reduced number of nephrons, but mostly a disorganized GBM (glomerular basement membrane) leading to proteinuria. Thus, ITGA3 is considered mostly a passive GBM stabilizer and not an active player in nephrogenesis. Recently, mutations in the human ITGA3 were shown to cause congenital nephrotic syndrome, epidermolysis bullosa and interstitial lung disease, otherwise termed NEP syndrome (Nephrotic syndrome, Epidermolysis bullosa and Pulmonary disease). Herein, we performed histological and molecular analysis on the kidneys of a single patient from the initial cohort harboring an ITGA3 mutation, to illuminate the role of ITGA3 in human renal development. We show the patient to harbor a unique phenotype at birth, including severe unilateral renal hypodysplasia. Interrogation of global gene expression in the hypodysplastic kidney versus three controls (fetal, child and adult kidneys) revealed perturbed expression in several renal developmental pathways implicated in hypodysplasia, including the Wnt, BMP (bone morphogenetic protein) and TGF (transforming growth factor) pathways. Moreover, the affected kidney showed upregulation of early embryonic genes (e.g. OCT4 and PAX8) concomitant with downregulated kidney differentiation markers, implying a defect in proper renal differentiation. In conclusion, we show for the first time that ITGA3 is not merely a passive anchor for renal ECM proteins, as predicted by mouse models. Instead, our results may suggest it plays a central role in the interplay of cells, morphogens and ECM, required for proper nephrogenesis, thus adding ITGA3 to the list of CAKUT (congenital anomalies of the kidney and urinary tract)-causing genes.
authors.affiliation: Pediatric Stem Cell Research Institute, Edmond and Lili Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel; Sheba Centers for Regenerative Medicine and Cancer Research, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Shukrun
authors.affiliation: Pediatric Stem Cell Research Institute, Edmond and Lili Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel; Sheba Centers for Regenerative Medicine and Cancer Research, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Asaf
authors.initials: A
authors.lastname: Vivante
authors.affiliation: Pediatric Stem Cell Research Institute, Edmond and Lili Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel; Sheba Centers for Regenerative Medicine and Cancer Research, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Oren
authors.initials: O
authors.lastname: Pleniceanu
authors.affiliation: Pediatric Stem Cell Research Institute, Edmond and Lili Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel; Sheba Centers for Regenerative Medicine and Cancer Research, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Einav
authors.initials: E
authors.lastname: Vax
authors.affiliation: Sheba Centers for Regenerative Medicine and Cancer Research, Sheba Medical Center, Ramat Gan, Israel; Department of Pediatrics and Pediatric Nephrology, Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Yair
authors.initials: Y
authors.lastname: Anikster
authors.affiliation: Pediatric Stem Cell Research Institute, Edmond and Lili Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel; Sheba Centers for Regenerative Medicine and Cancer Research, Sheba Medical Center, Ramat Gan, Israel; Department of Pediatrics and Pediatric Nephrology, Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Dekel
authors.affiliation: Pediatric Stem Cell Research Institute, Edmond and Lili Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel; Sheba Centers for Regenerative Medicine and Cancer Research, Sheba Medical Center, Ramat Gan, Israel; Department of Pediatrics and Pediatric Nephrology, Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Danny
authors.initials: D
authors.lastname: Lotan
mesh_terms: D000328:Adult; D000818:Animals; D004820:Epidermolysis Bullosa / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D039422:Integrin alpha3 / Q000235:genetics* / Q000378:metabolism; D007668:Kidney / Q000254:growth & development*; D008171:Lung Diseases / Q000235:genetics; D051379:Mice; D009154:Mutation; D009404:Nephrotic Syndrome / Q000235:genetics; D010641:Phenotype; D021381:Protein Transport
chemical_list: D039422:Integrin alpha3