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

Am J Hum Genet. 2020 Oct 1;107(4):753-762. doi: 10.1016/j.ajhg.2020.08.015.

Francesca Cristofoli ¹, Tonya Moss ², Hannah W Moore ³, Koen Devriendt ¹, Heather Flanagan-Steet ², Melanie May ², Julie Jones ², Filip Roelens ⁴, Carmen Fons ⁵, Anna Fernandez ⁵, Loreto Martorell ⁶, Angelo Selicorni ⁷, Silvia Maitz ⁸, Giuseppina Vitiello ⁹, Gerd Van der Hoeven ¹⁰, Steven A Skinner ³, Mathieu Bollen ¹⁰, Joris R Vermeesch ¹, Richard Steet ¹¹, Hilde Van Esch ¹²

Affiliations

1 Center for Human Genetics, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium.
2 JC Self Research Institute, Greenwood Genetic Center, 113 Gregor Mendel Circle, Greenwood, SC 29646, USA.
3 Greenwood Genetic Center, 106 Gregor Mendel Circle, Greenwood, SC 29646, USA.
4 Pediatric Neurology, Department of Pediatrics, AZ Delta, Brugsesteenweg 90, 8800 Roeselare, Belgium.
5 Pediatric Neurology Department, Sant Joan de Déu Hospital, Passeig de Sant Joan de Déu 2, 08950 Barcelona, Spain.
6 Department of Genetic and Molecular Medicine IPER, Institut de Recerca, Sant Joan de Déu Hospital, Passeig de Sant Joan de Déu 2, 08950 Barcelona, Spain.
7 Pediatric Department, ASST Lariana, Sant'Anna Hospital, Via Ravona 20, 22042 Como, Italy.
8 Clinical Pediatric Genetics Unit, MBBM Foundation, S. Gerardo Hospital, Via Pergolesi 33, 20900 Monza, Italy.
9 Department of Translational Medicine and Molecular Medicine and Medical Biotechnologies, Federico II University, via Pansini 5, 80131 Naples, Italy.
10 Laboratory of Biosignalling & Therapeutics, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
11 JC Self Research Institute, Greenwood Genetic Center, 113 Gregor Mendel Circle, Greenwood, SC 29646, USA. Electronic address: rsteet@ggc.org.
12 Center for Human Genetics, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium; Laboratory for the Genetics of Cognition, Department of Human Genetics, KU Leuven, Herestraat 49, 3000 Leuven, Belgium. Electronic address: hilde.vanesch@uzleuven.be.

PMID: 32910914 DOI: 10.1016/j.ajhg.2020.08.015

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 -3.6 to -12 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.

Keywords

LMNB1; intellectual disability; lamin A/C; lamin B1; microcephaly; mitotic spindle; nuclear envelope; nuclear lamina.

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