Cornelia de Lange Syndrome – Gene Mutations
© 2004 Prime Health Consultants, Inc.
The Cornelia de Lange syndrome (CdLS) (OMIM 122470) is characterized by a typical face (synophrys, upturned triangular nose, thin upper lip, long philtrum, downturned corner of the mouth), impaired growth, developmental delay, limb reduction defects, and anomalous development of the heart, eyes and genitourinary tract. It occurs de novo or may be transmitted as a dominantly inherited trait with variable expressivity. By studying families in which there were 2 or more affected members with a chromosome translocation or deletion, both groups of investigators localized the disorder to chromosome 5p13.1 and identified mutations in a gene termed “Nipped-B–like” or NIPBL. There were heterozygous missense, nonsense, deletion and insertion mutations of NIPBL, all of which would have resulted in a truncated or untranslated protein product. The normal product of this 47 exon gene has 2804 amino acids (termed by the Tonkin group “delangin”) that likely act upon chromosomes as an adherin, linking the interactions of promoters and enhancers of homeobox genes. Further studies revealed that the human gene and mouse homolog of NIPBL were expressed during gestation in the anlagen of the limbs, cranium and branchial arches, placenta, kidneys, liver, heart, skeletal muscle and thymus. Homologs of NIPBL were identified in flies, mosquitoes, worms, plants and fungi.
Characteristic features of CdLS (Reprinted with permission from: Krantz ID,
McCallum J, DeScipio C, et al. Nat Genet.2004;36:631–635. Copyright ©2004. Nature.)
First Editor’s Comment: Mutations in NIPBL were found in approximately 20% of patients with the clinical manifestations of the CdLS who were examined, implying that this disorder is likely to be genetically heterogeneous. Other sites that have been linked to the CdLS are located on chromosomes 2q37, 10p13, and 14q24, but an abnormality in one or more of the genes in these regions has not been detected to date. It is likely that as mutations in other genes that lead to the CdLS are identified, our understanding of the genetic regulation of somatic differentiation will be greatly enlarged.
Allen W. Root, MD
Second Editor’s Comment: The multiplicity of clinical features of CdLS, combined with reports of chromosomal rearrangements in some patients, had long suggested that CdLS might be a contiguous gene syndrome. These papers demonstrate that the clinical manifestations reflect the diverse functions of a single gene product—delangin—during development. Most of the reported cases have severe clinical phenotypes and mutations that predict full loss of function, such as frameshift mutations leading to premature stop of translation. However, in a few cases mutations predicted to alter some, but not all functions, ie, 3 bp deletion that would remove a single amino acid appears to produce milder features, suggesting that the manifestations reflect loss or alteration of specific functions related to different regions of delangin. Correlation of clinical findings with specific mutations in more patients, combined with experimental modeling of specific CdLS mutations in mice, should help to sort out the relationship between genotype and phenotype.
William A. Horton, MD