title: De novo and rare mutations in the HSPA1L heat shock gene associated with inflammatory bowel disease.
abstract: Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disease of the gastrointestinal tract which includes ulcerative colitis and Crohn's disease. Genetic risk factors for IBD are not well understood.
  
  
  
  We performed a family-based whole exome sequencing (WES) analysis on a core family (Family A) to identify potential causal mutations and then analyzed exome data from a Caucasian pediatric cohort (136 patients and 106 controls) to validate the presence of mutations in the candidate gene, heat shock 70 kDa protein 1-like (HSPA1L). Biochemical assays of the de novo and rare (minor allele frequency, MAF < 0.01) mutation variant proteins further validated the predicted deleterious effects of the identified alleles.
  
  
  
  In the proband of Family A, we found a heterozygous de novo mutation (c.830C > T; p.Ser277Leu) in HSPA1L. Through analysis of WES data of 136 patients, we identified five additional rare HSPA1L mutations (p.Gly77Ser, p.Leu172del, p.Thr267Ile, p.Ala268Thr, p.Glu558Asp) in six patients. In contrast, rare HSPA1L mutations were not observed in controls, and were significantly enriched in patients (P = 0.02). Interestingly, we did not find non-synonymous rare mutations in the HSP70 isoforms HSPA1A and HSPA1B. Biochemical assays revealed that all six rare HSPA1L variant proteins showed decreased chaperone activity in vitro. Moreover, three variants demonstrated dominant negative effects on HSPA1L and HSPA1A protein activity.
  
  
  
  Our results indicate that de novo and rare mutations in HSPA1L are associated with IBD and provide insights into the pathogenesis of IBD, and also expand our understanding of the roles of HSP70s in human disease.
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.|Rare Disease & LCM Laboratories, R & D Division, Daiichi Sankyo Co., Ltd, Tokyo, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Human Genetics and Genomic Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
authors.forename: Gaia
authors.initials: G
authors.lastname: Andreoletti
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Biology, Stanford University, Stanford, CA, USA.|Oncology Laboratories, Oncology Function, Daiichi Sankyo Co., Ltd, Tokyo, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Munehira
authors.affiliation: Department of Paediatric Gastroenterology, University Hospital Southampton NHS Foundation Trust, Southampton General Hospital, Tremona Road, Southampton, UK.
authors.forename: Akshay
authors.initials: A
authors.lastname: Batra
authors.affiliation: Department of Paediatric Gastroenterology, University Hospital Southampton NHS Foundation Trust, Southampton General Hospital, Tremona Road, Southampton, UK.
authors.forename: Nadeem A
authors.initials: NA
authors.lastname: Afzal
authors.affiliation: Department of Paediatric Gastroenterology, University Hospital Southampton NHS Foundation Trust, Southampton General Hospital, Tremona Road, Southampton, UK.
authors.forename: R Mark
authors.initials: RM
authors.lastname: Beattie
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Bernstein
authors.affiliation: Human Genetics and Genomic Medicine, University of Southampton, Southampton General Hospital, Southampton, UK. s.ennis@soton.ac.uk.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ennis
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. mpsnyder@stanford.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Snyder
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D002648:Child; D003093:Colitis, Ulcerative / Q000235:genetics* / Q000378:metabolism; D059472:Exome; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D044465:White People / Q000235:genetics
chemical_list: D018840:HSP70 Heat-Shock Proteins; C543454:HSPA1L protein, human
keywords: Crohn's disease; Exome; Sequencing; Ulcerative colitis