New cause of syndromic microcephaly identified
LMNB1 gene variants cause microcephaly by disrupting the nuclear envelope


Date:
September 17, 2020
Source:
Greenwood Genetic Center
Summary:
A team of international collaborators identifies a new cause of
syndromic microcephaly caused by LMNB1 mutations that disrupt the
nuclear envelope.



FULL STORY ========================================================================== Greenwood Genetic Center (GGC) researchers, in collaboration with
scientists from Belgium, Spain, and Italy, have confirmed that variants
in LMNB1 cause syndromic microcephaly with variable short stature,
intellectual disability, and other neurological symptoms. The findings are reported in the October issue of the American Journal of Human Genetics.


==========================================================================
The paper describes seven patients from five families with novel de novo variants in LMNB1, all with pronounced primary microcephaly as the core feature. Variants were identified through whole exome sequencing.

Functional analysis of each of the gene variants and resultant lamin B1
protein showed that these variants act in a dominant fashion to disrupt
nuclear envelope integrity which in turn causes the nucleus to become misshapen.

"We used a HeLa cell system to analyze the three missense mutations in
this gene and demonstrated impaired function of the nuclear lamina,"
said Tonya Moss, GGC research technologist and co-lead author along
with Francesca Cristofoli, PhD, of University Hospitals Leuven in
Belgium. "Two other variants displayed misshapen nuclei and a decrease
in nuclear localization of the lamin B1 protein, and another showed an increased frequency of condensed nuclei." Duplications in LMNB1 are
a known cause of autosomal dominant adult-onset leukodystrophy, but
this paper is the first to show that variants in this gene can cause
congenital abnormalities through nuclear envelope disruption.

"Because this gene product has multiple domains, it is likely that
different variants in LMNB1 will work by different mechanisms,
necessitating a case-by- case analysis of pathogenicity, which is
important for future treatment studies as well as reproductive planning
for families," said Richard Steet, PhD, co- corresponding author and
Director of Research at the JC Self Research Institute at GGC. "These
findings add LMNB1 to the growing list of genes implicated in severe
autosomal dominant microcephaly and broadens the phenotypic spectrum of
the laminopathies."

========================================================================== Story Source: Materials provided by Greenwood_Genetic_Center. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Francesca Cristofoli, Tonya Moss, Hannah W. Moore, Koen Devriendt,
Heather Flanagan-Steet, Melanie May, Julie Jones, Filip Roelens,
Carmen Fons, Anna Fernandez, Loreto Martorell, Angelo Selicorni,
Silvia Maitz, Giuseppina Vitiello, Gerd Van der Hoeven, Steven
A. Skinner, Mathieu Bollen, Joris R. Vermeesch, Richard Steet,
Hilde Van Esch. De Novo Variants in LMNB1 Cause Pronounced
Syndromic Microcephaly and Disruption of Nuclear Envelope
Integrity. The American Journal of Human Genetics, 2020; DOI:
10.1016/j.ajhg.2020.08.015 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200917105408.htm

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