title: Exome sequencing identified MYO1E and NEIL1 as candidate genes for human autosomal recessive steroid-resistant nephrotic syndrome.
abstract: To identify gene loci associated with steroid-resistant nephrotic syndrome (SRNS), we utilized homozygosity mapping and exome sequencing in a consanguineous pedigree with three affected siblings. High-density genotyping identified three segments of homozygosity spanning 33.6 Mb on chromosomes 5, 10, and 15 containing 296 candidate genes. Exome sequencing identified two homozygous missense variants within the chromosome 15 segment; an A159P substitution in myosin 1E (MYO1E), encoding a podocyte cytoskeletal protein; and an E181K substitution in nei endonuclease VIII-like 1 (NEIL1), encoding a base-excision DNA repair enzyme. Both variants disrupt highly conserved protein sequences and were absent in public databases, 247 healthy controls, and 286 patients with nephrotic syndrome. The MYO1E A159P variant is noteworthy, as it is expected to impair ligand binding and actin interaction in the MYO1E motor domain. The predicted loss of function is consistent with the previous demonstration that Myo1e inactivation produces nephrotic syndrome in mice. Screening 71 additional patients with SRNS, however, did not identify independent NEIL1 or MYO1E mutations, suggesting larger sequencing efforts are needed to uncover which mutation is responsible for the phenotype. Our findings demonstrate the utility of exome sequencing for rapidly identifying candidate genes for human SRNS.
authors.affiliation: Division of Nephrology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA. ss2517@columbia.edu
authors.forename: Simone
authors.initials: S
authors.lastname: Sanna-Cherchi
authors.forename: Katelyn E
authors.initials: KE
authors.lastname: Burgess
authors.forename: Shannon N
authors.initials: SN
authors.lastname: Nees
authors.forename: Gianluca
authors.initials: G
authors.lastname: Caridi
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Weng
authors.forename: Monica
authors.initials: M
authors.lastname: Dagnino
authors.forename: Monica
authors.initials: M
authors.lastname: Bodria
authors.forename: Alba
authors.initials: A
authors.lastname: Carrea
authors.forename: Maddalena A
authors.initials: MA
authors.lastname: Allegretta
authors.forename: Hyunjae R
authors.initials: HR
authors.lastname: Kim
authors.forename: Brittany J
authors.initials: BJ
authors.lastname: Perry
authors.forename: Maddalena
authors.initials: M
authors.lastname: Gigante
authors.forename: Lorraine N
authors.initials: LN
authors.lastname: Clark
authors.forename: Sergey
authors.initials: S
authors.lastname: Kisselev
authors.forename: Daniele
authors.initials: D
authors.lastname: Cusi
authors.forename: Loreto
authors.initials: L
authors.lastname: Gesualdo
authors.forename: Landino
authors.initials: L
authors.lastname: Allegri
authors.forename: Francesco
authors.initials: F
authors.lastname: Scolari
authors.forename: Vivette
authors.initials: V
authors.lastname: D'Agati
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Shapiro
authors.forename: Carmine
authors.initials: C
authors.lastname: Pecoraro
authors.forename: Teresa
authors.initials: T
authors.lastname: Palomero
authors.forename: Gian M
authors.initials: GM
authors.lastname: Ghiggeri
authors.forename: Ali G
authors.initials: AG
authors.lastname: Gharavi
mesh_terms: D016022:Case-Control Studies; D002884:Chromosomes, Human, Pair 15; D045647:DNA Glycosylases / Q000737:chemistry / Q000235:genetics*; D004252:DNA Mutational Analysis; D059472:Exome; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D007558:Italy; D008958:Models, Molecular; D020125:Mutation, Missense; D024461:Myosin Type I / Q000737:chemistry / Q000235:genetics*; D009404:Nephrotic Syndrome / Q000151:congenital* / Q000235:genetics; D009519:New York City; D010375:Pedigree; D010641:Phenotype; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D045647:DNA Glycosylases; C473634:NEIL1 protein, human; C511011:MYO1E protein, human; D024461:Myosin Type I