编码 GAR 结构域高度保守的锌结合残基的 MACF1 突变导致神经元迁移和轴突引导缺陷.

迄今为止, mutations in 15 actin- or microtubule-associated genes have been
associated with the cortical malformation lissencephaly and variable
brainstem hypoplasia. During a multicenter review, we recognized a rare
lissencephaly variant with a complex brainstem malformation in three
unrelated children. We searched our large brain-malformation databases and
found another five children with this malformation (as well as one with a
less severe variant), analyzed available whole-exome or -genome sequencing
数据, and tested ciliogenesis in two affected individuals. The brain
malformation comprised posterior predominant lissencephaly and midline
crossing defects consisting of absent anterior commissure and a striking
W-shaped brainstem malformation caused by small or absent pontine crossing
fibers. We discovered heterozygous de novo missense variants or an in-frame
deletion involving highly conserved zinc-binding residues within the GAR
domain of MACF1 in the first eight subjects. We studied cilium formation
and found a higher proportion of mutant cells with short cilia than of
control cells with short cilia. A ninth child had similar lissencephaly but
only subtle brainstem dysplasia associated with a heterozygous de novo
missense variant in the spectrin repeat domain of MACF1. 因此, we report
variants of the microtubule-binding GAR domain of MACF1 as the cause of a
distinctive and most likely pathognomonic brain malformation. A
gain-of-function or dominant-negative mechanism appears likely given that
many heterozygous mutations leading to protein truncation are included in
the ExAC Browser. 然而, three de novo variants in MACF1 have been
observed in large schizophrenia cohorts.