De Novo Variants in LMNB1 Cause Pronounced Syndromic Microcephaly and Disruption of Nuclear Envelope Integrity

Abstract

Lamin B1 plays an important role in the nuclear envelope stability, the regulation of gene expression, and neural development. Duplication of LMNB1, or missense mutations increasing LMNB1 expression, are associated with autosomal-dominant leukodystrophy. On the basis of its role in neurogenesis, it has been postulated that LMNB1 variants could cause microcephaly. Here, we confirm this hypothesis with the identification of de novo mutations in LMNB1 in seven individuals with pronounced primary microcephaly (ranging from À3.6 to À12 SD) associated with relative short stature and variable degree of intellectual disability and neurological features as the core symptoms. Simplified gyral pattern of the cortex and abnormal corpus callosum were noted on MRI of three individuals, and these individuals also presented with a more severe phenotype. Functional analysis of the three missense mutations showed impaired formation of the LMNB1 nuclear lamina. The two variants located within the head group of LMNB1 result in a decrease in the nuclear localization of the protein and an increase in misshapen nuclei. We further demonstrate that another mutation, located in the coil region, leads to increased frequency of condensed nuclei and lower steady-state levels of lamin B1 in proband lymphoblasts. Our findings collectively indicate that de novo mutations in LMNB1 result in a dominant and damaging effect on nuclear envelope formation that correlates with microcephaly in humans. This adds LMNB1 to the growing list of genes implicated in severe autosomal-dominant microcephaly and broadens the phenotypic spectrum of the laminopathies.

Molecular Genetics of Microcephaly Primary Hereditary: An Overview

“…In addition, LMNB1 and LMNB2 associate with the mitotic spindle; dominant negative mutant proteins that disrupt the organization of the filaments, impair the formation of the mitotic spindle [ 149 ]. Recently, dominant mutations in LMNB1 and LMNB2 have been shown to cause primary microcephaly [ 150 , 151 ]; the analysis of these variants in HeLa cells revealed defects in the formation of the nuclear envelope [ 150 ]. Interestingly, mice lacking Lmnb1 or Lmnb2 exhibit neuronal migration defects as well as reduced number of neuronal cells in the cerebral cortex [ 152 , 153 ].…”

Lamin B1 sequesters 53BP1 to control its recruitment to DNA damage

“…However, to date, no genetic disease associated with a decrease of lamin B1 level has been reported. Recently, it has been reported identification of de novo mutations in LMNB1 that result in a dominant and damaging effect on nuclear envelope formation and that cause microcephaly in humans ( 35 , 36 ). In contrast, various pathological situations have been associated with lamin B1 overexpression.…”

Nuclear Envelope Integrity in Health and Disease: Consequences on Genome Instability and Inflammation

“…Mutation in lamin genes can also cause neuropathies [ 138 , 139 , 140 , 141 ]. Other genetic diseases that causes neurological lesion are the tauopathies, which are neurodegenerative disorders characterized by the deposition of abnormal tau protein in the brain.…”