KATNB1 mutation redefines brain size

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Mutations in genes which cause the reduced size of brain and many other deformities is due to disruption of the normal process of human neurogenesis. Characterised by these mutations are conditions like microcephaly and ciliopathies, that occur when an important cellular mechanism controlled by cilia and centromeres in neurocortical development goes haywire. Many mutations that cause these conditions have been identified, but the interconnections between these regulations have been poorly understood.

Institute of Molecular and Cellular Biology A*STAR, Singapore scientists along with a collaboration of researchers from seven countries identify for the first time a gene responsible for a neuronal development disorder called microlissencephaly. It is a severe form of brain formation disorder wherein the subjects have smaller brains with fewer neurons than the well developed brain with severely reduced brain size, simplified gyri and enlarged ventricles of the brain. From three unrelated Middle Eastern countries, they were able to spot different mutations in the gene “KATNB1” causing severe microlissencephaly in children born to parents who were closely related relatives.

(Also read: Gene critical for brain development discovered)

MRI images of affected individuals show reduced size of various arts of the brain.  Image taken from the paper
MRI images of affected individuals show reduced size of various parts of the brain.
Image taken from the paper

From the study, they discovered that katanin p80 is a critical regulator of human brain development and extends its functions beyond regulation of microtubule severing and the mitotic spindle involved in normal cell division. Three independent mutations in KATNB1 affect protein levels and subcellular localization resulting in severe microlissencephaly in humans.

On a cellular level, loss of katanin p80 causes the formation of centrioles, which make up centromeres and regulate formation of cilia, which in excess leads to abnormal cell division. The limelight of the study was that katanin is a regulator of mother and daughter centriole number and that the presence of excessive centrioles, particularly mother centrioles in dividing neuroepithelial cells results in perturbed ciliary growth factor signalling, defective proliferation and excessive cell death owing to its marked effects.

Dr. Bruno Reversade from the Institute of Molecular and Cellular Biology A*STAR, Singapore quotes “Our discovery of the causative gene for this disease will benefit families as we are now able to provide premarital and prenatal diagnosis for parents,” as this study marked the emerging evidence to one of the questions on how neurodevelopment is affected genes linking centrosome, spindle, and cilia biology.

Source: A*STAR