genes associated with
Cornelia de Lange syndrome
of the disease
Cornelia de Lange Syndrome (CdLS) alters many aspects of growth and development. CdLS is caused by mutations in genes encoding proteins that ensure that chromosomes are distributed equally when a cell divides. These include genes that encode components of the cohesin complex, and Nipped-B-Like (NIPBL) that puts cohesin onto chromosomes. Individuals with CdLS have only modest reductions in the activities of these genes and do not show changes in chromosome distribution. Instead, they show differences in the expression many genes that control development. Drosophila, with one mutant copy of the Nipped-B gene, which is equivalent to the NIPBL gene, show characteristics similar to individuals with CdLS (Wu, 2015 and references therein).
Relevant studies of Cornelia de Lange syndrome
Wu, Y., Gause, M., Xu, D., Misulovin, Z., Schaaf, C.A., Mosarla, R.C., Mannino, E., Shannon, M., Jones, E., Shi, M., Chen, W.F., Katz, O.L., Sehgal, A., Jongens, T.A., Krantz, I.D. and Dorsett, D. (2015). Drosophila Nipped-B mutants model Cornelia de Lange syndrome in growth and behavior. PLoS Genet 11: e1005655. PubMed ID: 26544867
It was shown that although the external morphological changes in Nipped-B mutant Drosophila are minimal in an otherwise wild-type background, they share the reduced size with Nipbl(+/-) mice and CdLS. The data argue that the reduced size reflects decreases in both total cell number and size, and not changes in the systemic control of growth that sense critical body mass, deficits in the utilization of nutrition, or increased cell death. The decrease in size likely stems in part from modestly reduced expression of the myc (dm), Tor, InR and other genes that promote cell proliferation, division and growth, and not increased apoptosis. Indeed, one of the most intriguing findings is the reduced ability of excess dm expression to induce apoptosis in Nipped-B heterozygous mutants. This may stem in part from reduced function of a Dm-dependent enhancer that drives expression of the grim and reaper pro-apoptosis genes. This region binds Nipped-B and cohesin in wing discs, and deletion of this region permits excess dm expression using the tub-myc driver to increase wing size more than in wild-type flies because it reduced apoptosis (Wu, 2015).
It remains to be seen to what extent these findings in Drosophila might explain the reduced growth in CdLS and in Nipbl(+/-) mice. It seems likely that similar mechanisms at least make a significant contribution to the reduced growth in mammals because Nipbl(+/-) mice and cells from individuals with CdLS also show reduced c-myc expression. Organisms use a variety of mechanisms to sense body size and regulate growth and developmental transitions. Drosophila transitions are timed by pulses of the ecdysone steroid hormone produced by the prothoracic gland located between the two lobes of the brain. Specific neurons in the brain secrete a peptide hormone, prothoracicotropic hormone (PTTH) that stimulates ecdysone production. Insulin signaling, nutrition and many other factors, which are not all well understood, control the hormonal pathways and timing of the ecdysone pulses that determine absolute body size. For example, nutrient deprivation substantially delays the ecdysone pulses, but not enough to fully restore maximal body size. What is particularly striking is how close Nipped-B mutants are to wild type in their developmental timing and in how their developmental staging responds to nutrient deprivation. This argues that the systemic hormonal pathways that regulate body size and hormonal pulses that induce developmental stages are largely unaffected, and that the reduced size of Nipped-B mutants stems primarily from a small but significant reduction in the number of cell divisions, and in the mechanisms that determine final cell size (Wu, 2015).
It is more difficult to precisely time the developmental staging in mice and humans than in Drosophila, and thus to determine whether or not developmental timing or systemic growth pathways are significantly altered with decreased NIPBL function. Although some individuals with CdLS show slightly delayed puberty, puberty occurs at the normal age in many. The slight delays, and incomplete pubertal changes might all be attributed to causes other than a general developmental delay, such as structural abnormalities or changes in hormone levels. The relatively normal timing of puberty, therefore seems to indicates that the more extreme reductions in overall size observed in CdLS are also more likely to stem from changes in cell number and size than changes in systemic body size controls (Wu, 2015).
It was also found that Drosophila Nipped-B heterozygotes display many behavioral and neurological features resembling those seen in CdLS patients: they are deficient in learning and short-term memory, and display disruptive sleep patterns and abnormal circadian rhythms. Intellectual disability is the most common clinical phenotype seen in individuals with CdLS. The average IQ score of typical CdLS cases, mostly with NIPBL mutations, is 53 (range 30–86). It was found that although Nipped-B heterozygous mutant flies are capable of learning, their learning capacity is significantly lower than that of the wiso31 controls. Furthermore, these Nipped-B mutants are accompanied by pleiotropic structural abnormalities in mushroom bodies, the major brain structures controlling learning and memory. While it is conceivable that the morphological defects in the mushroom bodies could contribute to the learning and memory deficits observed in the Nipped-B mutants, how these structural and functional deficiencies correlate with each other warrant further detailed studies (Wu, 2015).
A striking similarity was observed in the sleep patterns of fly Nipped-B heterozygotes and those seen in CdLS patients. Sleep disturbances are common in CdLS and seen in up to 55% of CdLS individuals. Insomnia (difficulty in initiating sleep), difficulty staying asleep, frequent night wakenings, and sleepiness during the daytime are the most common sleep problems reported in CdLS. Frequent but dramatically shortened sleep episodes was the characteristic sleep pattern observed in Nipped-B heterozygote flies. In fact, the reduced length of sleep episodes lead to a dramatic loss in daytime and nighttime sleep, which was unable to be compensated for by significant increases in the number of sleep bouts (Wu, 2015).
While it has been speculated that sleep disturbances in CdLS individuals may be in part attributable to a circadian rhythm disorder, strict and objective studies to confirm this suggestion have not been undertaken. The locomotor activity-based circadian rhythm assay is a well-established measure of circadian rhythm in Drosophila. It was demonstrated that an aberrant circadian rhythm exists in a large fraction of Nipped-B haploinsufficient male and female flies. For Nipped-B mutants that still display rhythmic circadian patterns, their free-running activity rhythms are maintained at around 24 hours, similar to the periodicity of wiso31 controls. A remarkable consistency between the circadian defects and sleep aberrance was observed in these Nipped-B heterozygous mutants; flies that were profoundly arrhythmic were the ones that showed the most disturbed sleep patterns. Nevertheless, the circadian rhythm alterations are more apparent than the sleep disturbances in males, suggesting that additional sex-specific factors are involved in determining the sleep patterns. Taken together, these data suggest that at least in fly Nipped-B mutants, intrinsic circadian rhythm defects likely contribute to their aberrant sleep patterns (Wu, 2015).
Overall, this study on fly Nipped-B mutants demonstrates a strikingly analogous growth and neurocognitive/behavioral phenotype between heterozygous Nipped-B mutants and human CdLS individuals, including small body size, learning and memory deficits, disruptive sleep patterns and circadian rhythm defects. Drosophila Nipped-B heterozygotes are thus a valuable resource, with multiple objective and readily measureable metrics, for modeling human CdLS. Studies on the function of Nipped-B and cohesin components in CdLS patient cell lines, Nipbl(+/-) mouse and zebrafish models, and Drosophila have contributed substantially to our understanding of the roles of Nipped-B and cohesin components in development and gene regulation. The presence of a sophisticated genetic tool kit and economical availability of fruit flies will make it possible to explore developmental deficits in a tissue- and stage-specific manner, as well as to test their relevance to human development and the pathogenesis of CdLS. Drosophila is an ideal model organism to address these issues, given its short life cycle, lower degree of genomic redundancy and the available genetic tools. Nipped-B mutants can also be utilized to search for and test new pharmacologic therapeutic modalities, towards amelioration of the growth and neurodevelopmental functioning of individuals with CdLS (Wu, 2015).
Krantz, I.D., McCallum, J., DeScipio, C., Kaur, M., Gillis, L.A., Yaeger, D., Jukofsky, L., Wasserman, N., Bottani, A., Morris, C.A., Nowaczyk, M.J., Toriello, H., Bamshad, M.J., Carey, J.C., Rappaport, E., Kawauchi, S., Lander, A.D., Calof, A.L., Li, H.H., Devoto, M. and Jackson, L.G. (2004). Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B. Nat Genet 36: 631-635. PubMed ID: 15146186
The identification of mutations in a single allele of NIPBL in individuals with CdLS is consistent with a dominant pattern of inheritance. All mutations identified so far predict a truncated protein product and probably result in functional haploinsufficiency. That haploinsufficiency is a mechanism in CdLS is confirmed by the child with a large deletion of the region (encompassing NIPBL) and severe manifestations of CdLS, and by the child with the translocation reported in this study, who also has severe manifestations (Krantz, 2004).
Tonkin, E.T., Wang, T.J., Lisgo, S., Bamshad, M.J. and Strachan, T. (2004). 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 36: 636-641. PubMed ID: 15146185
Dorsett D. (2013). What fruit flies can tell us about human birth defects. Mo Med 110: 309-313. PubMed ID: 24003648
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Date revised: 8 Jan 2016
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