title: Father-to-daughter transmission of Cornelia de Lange syndrome caused by a mutation in the 5' untranslated region of the NIPBL Gene.
abstract: Cornelia de Lange syndrome (CdLS; also called Brachmann de Lange syndrome) is a developmental disorder characterized by typical facial dysmorphism, growth and mental retardation, microcephaly, and various malformations. Mutations in the NIPBL gene have been identified in approximately 40% of reported cases, suggesting either genetic heterogeneity or that some NIPBL mutations are not detected by current screening strategies. We screened a cohort of 21 patients with no previously identified NIPBL anomaly for mutations in the 5' untranslated region (5'UTR) and the proximal promoter of the NIPBL gene. We identified a heterozygous deletion-insertion mutation in exon 1, 321 nucleotides upstream of the translation initiation codon (c.-321_-320delCCinsA) in one affected girl and her mildly affected father. This mutation altered highly conserved nucleotides, was not found in 400 control alleles, arose de novo in the father, and cosegregated with the disease in the family. Using real-time quantitative PCR, we showed that NIPBL mRNA expression was lowered in patients' lymphocytes compared to control samples. Finally, we showed that, when subcloned into a luciferase reporter vector, the mutation leads to a significant reduction of reporter gene activity. Our results demonstrate that mutations in the 5' noncoding region of the NIPBL gene can be involved in the pathogenesis of CdLS. Mutations affecting this region of the gene might be associated with a milder phenotype.
authors.affiliation: INSERM U781 and Département de Génétique, Hôpital Necker-Enfants Malades, Paris, France. borck@necker.fr
authors.forename: Guntram
authors.initials: G
authors.lastname: Borck
authors.forename: Mohamed
authors.initials: M
authors.lastname: Zarhrate
authors.forename: Céline
authors.initials: C
authors.lastname: Cluzeau
authors.forename: Elodie
authors.initials: E
authors.lastname: Bal
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Bonnefont
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
authors.forename: Laurence
authors.initials: L
authors.lastname: Colleaux
mesh_terms: D020121:5' Untranslated Regions; D000293:Adolescent; D018797:Cell Cycle Proteins; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D018899:CpG Islands; D003635:De Lange Syndrome / Q000235:genetics*; D005260:Female; D017930:Genes, Reporter; D018740:Genetic Heterogeneity; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D040582:Inheritance Patterns; D008156:Luciferases / Q000032:analysis; D008297:Male; D009154:Mutation; D010375:Pedigree; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D020121:5' Untranslated Regions; D018797:Cell Cycle Proteins; C487465:NIPBL protein, human; D011506:Proteins; D012333:RNA, Messenger; D008156:Luciferases