The major components of the nuclear lamina are type V intermediate filament proteins grouped in two distinct classes, namely A- and B-type lamins. In mammals, B-type lamins are encoded by two distinct genes (LMNB1[MIM: 150340] and LMNB2[MIM: 150341]), and expressed in almost all known cell types beginning at earliest stages of development.
The LMNB2mutations causing the progressive myoclonic epilepsy syndrome are recessively inherited homozygous missense mutations.
The LMNB2mutations causing the severe microcephaly syndrome are heterozygous, and almost all of them arose de novo. To date, all mutations are missense mutations.
Functional characterization of several different missense variants demonstrated that these variants appear to disrupt the integrity of the nuclear envelope leading to defects in the assembly of the highly ordered fibrous arrays typically formed by wild-type lamin B2 protein. This data suggests that disruption of the organisation of the nuclear lamina in neurons, perhaps through abnormal neuronal migration, leads to the neurodevelopmental phenotypes. It is hypothed that the mutations act in a dominant-negative way. A molecular explanation for the two genotype-phenotype groups has not yet emerged.
Diagnosis/testing
Mutations in LMNB2 can be identified using molecular genetic testing, either directly by sequencing of the gene or by gene panel or genome-wide (e.g., exome/genome) sequencing.
LMNB2