Question

Agenetics student visiting a museum saw a painting by Goya showing a woman with a newborn baby in her lap who had very short arms and legs along with some facial abnormalities. Wondering whether this condition might be a genetic disorder, the student went online, learning that the baby might have Roberts syndrome (RBS), a rare autosomal recessive trait. She read that cells in RBS have mitotic errors, including the premature separation of centromeres and other heterochromatic regions of homologs in metaphase instead of anaphase. As a result, metaphase chromosomes have a rigid, or “railroad track” appearance. RBS has been shown to be caused by mutant alleles of the ESCO2 gene, which functions during cell division. The student wrote a list of questions to investigate in an attempt to better understand this condition. How would you answer these questions? 1. What do centromeres and other heterochromatic regions have in common that might cause this appearance? 2. What might be the role of the protein encoded by ESCO2, which in mutant form could cause these changes in mitotic chromosomes? 3. How could premature separation of centromeres cause the problems seen in RBS?

Answer 1

1. Centromeres and heterochromatin are both extremely condensed regions of the genome. These are regions of DNA that are densely packed by histones and other proteins.

Both heterochromatin and centromeres contain  di- and tri-methylation of histones H3K9, H3K27, mono methylation on Lysine residues of histones.

These modifications and heterochromatinisation at centromeres allow binding of cohesins like SMC3 which play an important role in holding the sister chromatids together during mitosis.

Defects in any of the above given components cause mis-seggregation of sister chromatids leading to programmed cell death, delay in mitosis, ploidy disorders.

2. ESCOS2 plays a role in gluing the sister chromatids during mitosis. ESCOS2 is an acetyl transferase that acetylates a cohesin component SMC3. This is necessary for pairing of sister chromatids after replication. Cohesins are the glue that keep the sustes chromatids together and ESCOS2 function is required for establishing sister chromatid cohesion.

Hence, mutants in ESCOS2 lack functional ESCOS2 protein and this causes some of the glue between sister chromatids to be missing around the chromosome's constriction point. This leads to premature separation of chromatids leading to delayin mitosis or in extreme cases, ploidy defects.

3. ESCOS2 mutations lead to premature separation of centromeres. Dividing cells respond to this by delaying mitosis and delayed cell division can be a signal that the cell should undergo self-destruction. The symptoms of RBS may result from loss of certain cells and tissues during early embryonic development. Premature separation of centromeres also cause ploidy defects which might cause symptoms of RBS.