SMC1L1 Mutations in Cornelia de Lange Syndrome

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The Cornelia de Lange syndrome ([CDLS] OMIM 122470, also termed the Brachmann-de Lange syndrome) was first described in 1916. It is characterized by intrauterine and post-natal growth retardation, developmental delay, anomalies of the upper limbs, microcephaly, very low anterior and posterior hairlines, and typical facial features of synophrys, anteverted nostrils, long eyelashes, long filtrum, thin vermillion borders, and crescent-shaped mouth. Although CDLS occurs sporadically predominantly, both autosomal dominant (with variable penetrance or germ-line mosaicism) and X-linked familial forms of this syndrome have been identified. The disorder has been linked to genetic mutations in the cohesin complex of proteins that are essential for normal segregation of chromosomes during mitosis. In man, sister chromatids are connected to one another from formation until separation in the anaphase of the cell cycle. The cohesin protein family (composed of SMC1L1 [structural maintenance of chromosomes-like], SMC3, SCC1, SA1, SA2, and NIPBL) partially dissociates from chromatin during prophase; cohesins near the centromere leave the chromosome during metaphase and are completely removed at the onset of anaphase (OMIM 606452). The structure of some of the cohesins (SMC1L1, OMIM 300040) is similar to that of force-generating proteins such as myosin and kinesin. Mutations in NIPBL (OMIM 608667, chromosome 5p13.1) are associated with many of the sporadic and autosomal forms of CDLS. 1,2 Musio et al 3 demonstrated that the X-linked form of CDLS is due to a loss-of-function mutation in SMC1L1 (chromosome Xp11.22-p11.21), encoding a cohesion complex protein that forms a ring-like structure with other components that then interacts with DNA. In 24 of the 54 patients with CDLS, the researchers detected mutations in NIPBL; in 4 affected members of one family and in one patient with sporadic CDLS, the investigators detected mutations within SMC1L1 - a 3 nt deletion (N:2493-2495) in the familial cases resulting in deletion of residue Gln832 and an Asp831Glu mutation and an A to C transversion at nt 1478, resulting in a missense Glu493Ala substitution in the sporadic CDLS patient. It was suggested that both mutations resulted in decreased expression of the parent gene, reasoning that a null mutation in SMC1L1 would result in non-viability.

Musio A, Selicorni A, Focarelli ML, et al. X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations. Nat Genet. 2006;38:528-30.

Editor’s Comment

In 28 of the 54 patients with CDLS, Musio et al did not identify a genetic abnormality suggesting that as yet unrecognized mutations in genes other than NIPBL and SMC1L1 (perhaps other members of the cohesion complex) also result in the CDLS phenotype. The Roberts syndrome (OMIM 268300) has a phenotype somewhat similar to that of CDLS and is due to mutation in a gene ( ECO2, OMIM 609353) that is necessary for correct alignment of the sister chromatid cohesion complex. Thus, it is likely that dysfunctional mutations within the family of genes encoding components of the cohesion complex and their related partners leads to several clinically-related disorders in a manner similar to that of mutations within the mitogen-activated protein kinase pathway. 3 Related disorders due to abnormalities of genes encoding factors that contribute to the formation, orientation, chromatin interaction, and function of the cohesin complex are likely to be found in future studies, although in many instances mutations in this system are likely to result in non-viable conceptuses. NIPBL also activates homeobox genes and is involved in the regulation of development. Similarly, SMC1L1 also has multiple functions within the realms of genome stability, DNA repair, and gene expression.

Allen W. Root, MD

References - (linked to )

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Last Updated: 04/30/2008