Autosomal recessive primary microcephaly due to ASPM mutations: An update

Abstract

Autosomal recessive microcephaly or microcephaly primary hereditary (MCPH) is a genetically heterogeneous neurodevelopmental disorder characterized by a reduction in brain volume, indirectly measured by an occipitofrontal circumference (OFC) 2 standard deviations or more below the age- and sex-matched mean (-2SD) at birth and -3SD after 6 months, and leading to intellectual disability of variable severity. The abnormal spindle-like microcephaly gene (ASPM), the human ortholog of the Drosophila melanogaster "abnormal spindle" gene (asp), encodes ASPM, a protein localized at the centrosome of apical neuroprogenitor cells and involved in spindle pole positioning during neurogenesis. Loss-of-function mutations in ASPM cause MCPH5, which affects the majority of all MCPH patients worldwide. Here, we report 47 unpublished patients from 39 families carrying 28 new ASPM mutations, and conduct an exhaustive review of the molecular, clinical, neuroradiological, and neuropsychological features of the 282 families previously reported (with 161 distinct ASPM mutations). Furthermore, we show that ASPM-related microcephaly is not systematically associated with intellectual deficiency and discuss the association between the structural brain defects (strong reduction in cortical volume and surface area) that modify the cortical map of these patients and their cognitive abilities.

Delineation of MidXq28‐duplication syndrome distal to MECP2 and proximal to RAB39B genes

“…Noteworthy, ASPM mutations cause MCPH5-microcephaly. 16 MCPH5 associates with gyral pattern simplification, partial CC agenesis and mild/moderate cerebellar and/or pontine hypoplasia, 17 as observed in two of our cases.…”

A New Way to Treat Brain Tumors: Targeting Proteins Coded by Microcephaly Genes?

“…Nearly all of the identified 150+ identified mutations lead to ASPM truncation, primarily as a result of nonsense or frameshift mutations [74] . Although the mutations affect all tissues, for unclear reasons, ASPM is particularly important to neural stem/progenitor cells compared to other proliferating cells [65, 75] .…”

“…Indeed, Aspm -null mice develop microcephaly and hypogonadism, but other tissues seem relatively unaffected [70, 76] . Similarly, individuals with homozygous ASPM mutations uniformly exhibit microcephaly and neurocognitive disorders, with varying degrees of other pathology such as behavioral problems, seizures, and rarely various organ malformations [74] . Research into the molecular function of ASPM indicates that microcephaly associated with ASPM mutation is due a combination of increased apoptosis and impaired self-renewal of neural stem and progenitor cells [69–71] .…”

Digenic inheritance of human primary microcephaly delineates centrosomal and non‐centrosomal pathways

“…Eighteen genes have been reported to cause MCPH (Naveed et al, 2018). ASPM is the most common, followed by WDR62 (Létard et al, 2018). Many PM-causing gene products, including ASPM and WDR62, are localized at the centrosome during interphase or spindle pole during mitosis and are hence believed to cause PM by a common, centrosomal mechanism (Barbelanne & Tsang, 2014;Megraw, Sharkey, & Nowakowski, 2011).…”