Heterozygous lamin B1 and lamin B2 variants cause primary microcephaly and define a novel laminopathy

Abstract

Purpose Lamins are the major component of nuclear lamina, maintaining structural integrity of the nucleus. Lamin A/C variants are well established to cause a spectrum of disorders ranging from myopathies to progeria, termed laminopathies. Phenotypes resulting from variants in LMNB1 and LMNB2 have been much less clearly defined. Methods We investigated exome and genome sequencing from the Deciphering Developmental Disorders Study and the 100,000 Genomes Project to identify novel microcephaly genes. Results Starting from a cohort of patients with extreme microcephaly, 13 individuals with heterozygous variants in the two human B-type lamins were identified. Recurrent variants were established to be de novo in nine cases and shown to affect highly conserved residues within the lamin ɑ-helical rod domain, likely disrupting interactions required for higher-order assembly of lamin filaments. Conclusion We identify dominant pathogenic variants in LMNB1 and LMNB2 as a genetic cause of primary microcephaly, implicating a major structural component of the nuclear envelope in its etiology and defining a new form of laminopathy. The distinct nature of this lamin B–associated phenotype highlights the strikingly different developmental requirements for lamin paralogs and suggests a novel mechanism for primary microcephaly warranting future investigation.

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 ].…”

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.…”

From the Matrix to the Nucleus and Back: Mechanobiology in the Light of Health, Pathologies, and Regeneration of Oral Periodontal Tissues

“…Lamins are IFs in the nucleus and are encoded by three genes in men: LMNA, LMNB1 and LMNB2. LMNA encodes for the two protein isoforms, Lamin A and Lamin C. Lamin B1 and Lamin B2 are the corresponding gene products of LMNB1 and LMNB2, respectively [189,190]. All Lamin types form a tight meshwork of filaments of approximately 10-30 nm thickness along the INM [191].…”