Father-to-daughter transmission of Cornelia de Lange syndrome caused by a mutation in the 5′ untranslated region of theNIPBL 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.

Prenatal/neonatal pathology in two cases of Cornelia de Lange syndrome harboring novel mutations of NIPBL

“…Mutational screening carried out in patients affected by CdLS demonstrated the occurrence of frameshift, nonsense, missense, intron splicing mutations, and 5=-untranslated region mutations 22 at a frequency ranging from 35% 6 to 56%, 7 and preliminary phenotypic differences between mutationpositive and mutation-negative individuals were identified. The results so far obtained also suggest a trend toward a more severe clinical phenotype in NIPBL-mutated patients and, within this group, a milder phenotype in individuals with missense and 5=-untranslated region mutations compared with other types.…”

Incidence and clinical features of X-linked Cornelia de Lange syndrome due toSMC1L1 mutations

“…NIPBL maps to chromosome 5p13.2 and encodes delangin, the mammalian ortholog of Drosophila Nipped-B and yeast Scc2 which are both involved in sister chromatid cohesion by loading cohesin complexes onto chromatin (Strachan, 2005;Dorsett, 2006). CdLS-causing mutations are scattered throughout this large gene and include nonsense, frameshift, splice site, and missense DOI: 10.1002/humu.9478 mutations, as well as a mutation in the 5'untranslated region (5'UTR) and small in-frame deletions (Borck et al, 2004;Gillis et al, 2004;Krantz et al, 2004;Tonkin et al, 2004;Miyake et al, 2005;Bhuiyan et al, 2006;Borck et al, 2006;Yan et al, 2006). Absence of NIPBL mutations in half of affected persons suggested genetic heterogeneity in CdLS.…”

Cohesin and Human Disease

“…In rare cases, researchers have found large genomic rearrangements as well as alterations in the upstream noncoding region of the gene. For example, one affected girl and her mildly affected father have a heterozygous deletion-insertion mutation in the NIPBL 5′-untranslated region (UTR) ( 9 ), and in another patient multiplex ligation-dependent probe amplification (MLPA) revealed a 5.2-kb deletion that encompasses exons 41-42 of NIPBL ( 6 ). Among NIPBL mutationnegative CdLS probands approximately 8% (4% of the total CdLS population) carry an SMC1A mutation ( 19 ).…”