Genetic Primary Microcephalies: When Centrosome Dysfunction Dictates Brain and Body Size
Sarah Farcy1,2, Hassina Hachour3, Nadia Bahi-Buisson4,5
1UMR144, Institut Curie, 75005 Paris, France.
Abstract:
Primary microcephalies (PMs) are defects in brain growth that are detectable at or before birth and are responsible for neurodevelopmental disorders. Most are caused by biallelic or, more rarely, dominant mutations in one of the likely hundreds of genes encoding PM proteins, i.e., ubiquitous centrosome or microtubule-associated proteins required for the division of neural progenitor cells in the embryonic brain. Here, we provide an overview of the different types of PMs, i.e., isolated PMs with or without malformations of cortical development and PMs associated with short stature (microcephalic dwarfism) or sensorineural disorders. We present an overview of the genetic, developmental, neurological, and cognitive aspects characterizing the most representative PMs. The analysis of phenotypic similarities and differences among patients has led scientists to elucidate the roles of these PM proteins in humans. Phenotypic similarities indicate possible redundant functions of a few of these proteins, such as ASPM and WDR62, which play roles only in determining brain size and structure. However, the protein pericentrin (PCNT) is equally required for determining brain and body size. Other PM proteins perform both functions, albeit to different degrees. Finally, by comparing phenotypes, we considered the interrelationships among these proteins.
Insights
Primary microcephalies (PMs) are rare brain growth defects caused by genetic mutations. Understanding these conditions helps reveal the complex roles of proteins in brain development and overall growth.
Area of Science:
- Genetics
- Developmental Biology
- Neuroscience
Background:
- Primary microcephalies (PMs) are congenital brain growth defects leading to neurodevelopmental disorders.
- These conditions often result from mutations in genes encoding centrosome or microtubule-associated proteins crucial for neural progenitor cell division.
Purpose of the Study:
- To provide an overview of various types of primary microcephalies.
- To analyze the genetic, developmental, neurological, and cognitive characteristics of representative PMs.
- To elucidate the functions and interrelationships of PM proteins in human development.
Main Methods:
- Review and synthesis of existing literature on primary microcephalies.
- Comparative analysis of patient phenotypes to understand protein functions.
- Examination of genetic, developmental, neurological, and cognitive data.
Main Results:
- PMs present diverse phenotypes, including isolated forms, those with cortical malformations, microcephalic dwarfism, and sensorineural disorders.
- Proteins like ASPM and WDR62 primarily influence brain size and structure, suggesting functional redundancy.
- Pericentrin (PCNT) is essential for both brain and body size determination, highlighting varied protein roles.
Conclusions:
- Phenotypic comparisons reveal the distinct and overlapping functions of PM proteins.
- Understanding these proteins is key to deciphering mechanisms of brain and body size regulation.
- Further research into PM protein interrelationships can illuminate neurodevelopmental pathways.
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