TABLE 1.
MCPH genes and proteins and their involvement in the regulation of the mitotic spindle, cell cycle control and/or chromosome segregation.
| Locus/Gene name | Clinical features in humans | Protein | Intracellular Localization | Known Function | |
|---|---|---|---|---|---|
| Major neurological signs | Short stature | ||||
|
MCPH1 MCPH1 |
Severe PM, ID, premature chromosome condensation | ++ | MICROCEPHALIN | Nucleus, cytoplasm, centrosome depending on the isoform and cell type | DNA Damage response, transcription, cell cycle control, Spindle pole orientation |
| MCPH2/WDR62 | Normal OFC to severe PM, seizures, spastic quadriparesis, severe ID, cortical malformations (polymicrogyria, schizencephaly, nodular or subcortical heterotopia) | no | WDR62 | Spindle pole, centrosome, centriole, nucleus | Centriole duplication, spindle pole orientation |
| MCPH3/CDK5RAP2 | Severe PM, sensorineural hearing loss, ID | + | CDK5RAP2 | Centrosome (PCM) | Spindle pole orientation, PCM maturation, microtubule nucleation, Centriole engagement |
| MCPH4/KNL1 | Severe PM, ID | no | KNL1 | Kinetochore | Kinetochore, microtubule attachment |
| MCPH5/ASPM | Severe PM, ID, gyral simplification | no | ASPM | Spindle pole | Spindle pole orientation & integrity |
| MCPH6/CENPJ | Severe PM, short stature, Seckel syndrome, ID | +++ | CENPJ | Centriole | Centriole duplication |
| MCPH7/STIL | Severe PM, ID | +++ | STIL | Centriole | Centriole duplication |
| MCPH8/CEP135 | Severe PM, ID | ++ | CEP135 | Centriole | Centriole duplication |
| MCPH9/CEP152 | Severe PM, ID | +++ | CEP152 | Centriole | Centriole duplication |
| MCPH10/ ZNF335 | Severe PM, ID, seizures, brainstem hypoplasia | no | ZNF335 | Nucleus (histone methyltransferase complex protein) | Transcription |
| MCPH11/PHC1 | Severe PM, ID | + | PHC1 | Nucleus (Polycomb group multiprotein PRC1-like complex protein) | Transcription |
| MCPH12/CDK6 | Severe PM, ID | no | CDK6 | Nucleus (kinase activity), centrosome | Cell cycle control |
| MCPH13/CENPE | Severe PM, ID, gyral simplification, cerebellar hypoplasia | +++ | CENPE | Kinetochore, mitotic spindle | Kinetochore microtubule attachment, chromosomes congression |
| MCPH14/SASS6 | Severe PM, ID | ++ | SASS6 | Centriole | Centriole duplication |
| MCPH15/MFSD2A | Severe PM, seizures, spastic tetraparesis, hydrocephaly, thin cortex, brainstem hypoplasia | no | MFSD2A | BBB in endothelial cells | Brain uptake of DHA / fatty acids |
| MCPH16/ANKLE2 | Severe PM, ID, seizures, spastic tetraparesis | ++ | ANKLE2 | Nuclear envelope, ER | Nuclear envelope reassembly in late anaphase |
| MCPH17/CIT | Severe PM, ID, spastic tetraparesis, microlissencepaly | no | CIT | Midbody | Cytokinesis |
| MCPH18/WDFY3 | PM, ID | na | WDFY3 | Autophagic structures | Macroautophagy |
| MCPH19/COPB2 | Severe PM, ID, spastic tetraparesis, cortical blindness, gyral simplification | no | COPB2 | Golgi coatomer complex COPI | Retrograde Golgi to ER transport of vesicles |
| MCPH20/KIF14 | Severe PM, ID, spastic tetraparesis, gyral simplification | + | KIF14 | Microtubule motor protein, microtubules, spindle pole, midbody | Cytokinesis Chromosome congression, |
| MCPH21/NCAPD2 | Severe PM, severe ID, seizures, autism | +++ | NCAPD2 | Chromatin (condensin multiprotein complex) | Chromatin condensation during mitosis |
| MCPH22/NCAPD3 | Severe PM, mild to severe ID, seizures | ++ | NCAPD3 | Chromatin (condensin multiprotein complex) | Chromatin condensation during mitosis |
| MCPH23/NCAPH | PM, ID | no | NCAPH | Chromatin (condensin multiprotein complex) | Chromatin condensation during mitosis |
| MCPH24/NUP37 | Severe PM, mild ID, vermis hypoplasia | no | NUP37 | Nuclear envelope (NPC), kinetochore during mitosis | NPC, kinetochore microtubule attachment |
| MCPH25/MAP11 | Severe PM, ID | no | MAP11 | Microtubule associated protein, spindle pole | Spindle dynamics |
MCPH proteins for which no association with the mitotic spindle, cell cycle control and/or chromosome segregation has been documented so far are mentioned in light grey background. PM: Primary Microcephaly; ID: intellectual disability; OFC: occipito-frontal circumference; PCM: pericentriolar matrix; BBB: blood-brain barrier, DHA: docosahexaenoic acid; ER: endoplasmic reticulum; NPC: nuclear pore complexes; na: non-available.