Protein-Truncating Mutations in ASPM Cause Variable Reduction in Brain Size

Abstract

Mutations in the ASPM gene at the MCPH5 locus are expected to be the most common cause of human autosomal recessive primary microcephaly (MCPH), a condition in which there is a failure of normal fetal brain development, resulting in congenital microcephaly and mental retardation. We have performed the first comprehensive mutation screen of the 10.4-kb ASPM gene, identifying all 19 mutations in a cohort of 23 consanguineous families. Mutations occurred throughout the ASPM gene and were all predicted to be protein truncating. Phenotypic variation in the 51 affected individuals occurred in the degree of microcephaly (5-11 SDs below normal) and of mental retardation (mild to severe) but appeared independent of mutation position.

Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target

“…ASPM also has been recognized as a critical regulator of brain size, likely via its role in promoting neuroblast proliferation and symmetric division (28)(29)(30)45). Our data showing that neural stem cell differentiation results in loss of ASPM expression and that siRNAmediated knockdown of ASPM specifically inhibits neural stem cell self renewal and glioblastoma growth suggests the possibility that this gene may be involved in glioblastoma pathogenesis by promoting a stem cell phenotype.…”

“…This led us to study the ASPM gene, because it had the highest K value in both glioblastoma data sets of any gene that has not been previously recognized as a cancer target. ASPM is the human ortholog of a Drosophila mitotic spindle protein, encoding the protein microcephalin (28)(29)(30). ASPM is thought to regulate neuroblast proliferation (29), and it has recently been shown to be a key regulator of brain size through evolution (31)(32)(33).…”

“…ASPM is the human ortholog of a Drosophila mitotic spindle protein, encoding the protein microcephalin (28)(29)(30). ASPM is thought to regulate neuroblast proliferation (29), and it has recently been shown to be a key regulator of brain size through evolution (31)(32)(33). Mutations within this gene are associated with primary human microcephaly (29,30).…”

“…ASPM is thought to regulate neuroblast proliferation (29), and it has recently been shown to be a key regulator of brain size through evolution (31)(32)(33). Mutations within this gene are associated with primary human microcephaly (29,30). A recent study demonstrated increased ASPM in ovarian and uterine cancers, suggesting that it may play a role in other cancer types (34), although it was not part of the MS of undifferentiated cancer (15), suggesting that it may have specificity for only a few tumor types including glioblastoma.…”

Brain shape in human microcephalics and Homo floresiensis

“…Affected individuals have been reported from all over the world, frequently from consanguineous unions (9,10,(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Traditionally, the terms ''primary microcephaly,'' ''true microcephaly,'' ''microcephaly vera,'' and ''primary autosomal recessive microcephaly'' (MCPH, MIM #251200; Online Mendelian Inheritance in Man, www.ncbi.nlm.nih.gov/omim) have been used to describe individuals who were born with abnormally small brains, sloping foreheads, and prominent ears but lacked other ''neurological, growth, health, or dysmorphic findings, and [had] no discernible prenatal or postnatal syndrome or cause, such as an aberrant chromosome or structural brain anomaly'' (16).…”