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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.)
Krantz ID, McCallum J, DeScipio C, et al. Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melangaster Nipped-B. Nat Genet. 2004;36:631–635.
Tonkin ET, Wang T-J, Lisgo S, et al. NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B is mutated in Cornelia de Lange syndrome. Nat Genet. 2004;36:636–641.
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
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Current GGH - Vol. 24 No. 1
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