title: A SPRY2 mutation leading to MAPK/ERK pathway inhibition is associated with an autosomal dominant form of IgA nephropathy.
abstract: IgA nephropathy (IgAN) represents the most common primary glomerulonephritis worldwide with a prevalence of 25-50% among patients with primary glomerulopathies. In ~5-10% of the patients the disease segregates with an autosomal dominant (AD) pattern. Association studies identified loci on chromosomes 1q32, 6p21, 8p23, 17p13, 22q12, whereas classical linkage studies on AD families identified loci on chromosomes 2q36, 4q26-31, 6q22, 17q12-22. We have studied a large Sicilian family where IgAN segregates with an AD transmission. To identify the causal gene, the exomes of two affected and one unaffected individual have been sequenced. From the bioinformatics analysis a p.(Arg119Trp) variant in the SPRY2 gene was identified as the probable disease-causing mutation. Moreover, functional characterization of this variant showed that it is responsible for the inhibition of the MAPK/ERK1/2 pathway. The same effect was observed in two sporadic IgAN patients carriers of wild-type SPRY2, suggesting that downregulation of the MAPK/ERK1/2 pathway represents a common mechanism leading to IgAN.
authors.affiliation: Institute of Medical Genetics, Catholic University, Rome, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Milillo
authors.affiliation: Institute of Medical Genetics, Catholic University, Rome, Italy.
authors.forename: Francesca
authors.identifier: http://orcid.org/0000-0002-1120-9307
authors.initials: F
authors.lastname: La Carpia
authors.affiliation: Division of Nephrology and Dialysis Columbus-Gemelli University Hospital, Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Costanzi
authors.affiliation: Institute of Medical Genetics, Catholic University, Rome, Italy.
authors.forename: Vanessa
authors.initials: V
authors.lastname: D'Urbano
authors.affiliation: Division of Anatomic Pathology and Histology, Catholic University, Rome, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Martini
authors.affiliation: Department of Medicine and Aging Science, School of Medicine and Health Sciences, University 'G. d'Annunzio', Chieti, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Lanuti
authors.affiliation: Division of Nephrology and Dialysis Columbus-Gemelli University Hospital, Rome, Italy.
authors.forename: Gisella
authors.initials: G
authors.lastname: Vischini
authors.affiliation: Division of Anatomic Pathology and Histology, Catholic University, Rome, Italy.
authors.forename: Luigi M
authors.identifier: http://orcid.org/0000-0003-1739-4758
authors.initials: LM
authors.lastname: Larocca
authors.affiliation: Department of Medicine and Aging Science, School of Medicine and Health Sciences, University 'G. d'Annunzio', Chieti, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Marchisio
authors.affiliation: Department of Medicine and Aging Science, School of Medicine and Health Sciences, University 'G. d'Annunzio', Chieti, Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Miscia
authors.affiliation: Department of Medical Sciences, University of Torino, Torino, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Amoroso
authors.affiliation: Institute of Medical Genetics, Catholic University, Rome, Italy.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Gurrieri
authors.affiliation: Institute of Medical Genetics, Catholic University, Rome, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Sangiorgi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D002648:Child; D015536:Down-Regulation; D059472:Exome; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D005922:Glomerulonephritis, IGA / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C485561:SPRY2 protein, human