期刊
GENETICS IN MEDICINE
卷 23, 期 2, 页码 408-414出版社
ELSEVIER SCIENCE INC
DOI: 10.1038/s41436-020-00980-3
关键词
LMNB1; LMNB2; laminopathy; primary microcephaly; neurodevelopmental disorder
资金
- European Union's Horizon 2020 research and innovation program European Research Council (ERC) Advanced Grant [788093]
- Medical Research Council (MRC) Unit core grant [U127580972]
- MRC Career Development Award [MR/M02122X/1]
- Lister Institute Research Prize Fellowship
- Health Education England Genomics Education Programme research fellowship
- Health Innovation Challenge Fund [HICF-1009-003]
- Wellcome
- National Institute for Health Research
- NHS England
- Wellcome Trust
- Cancer Research UK
- Medical Research Council
- European Research Council (ERC) [788093] Funding Source: European Research Council (ERC)
- MRC [MC_UU_00007/5, MR/S006753/1, MR/M02122X/1] Funding Source: UKRI
This study identified dominant pathogenic variants in LMNB1 and LMNB2 as a genetic cause of primary microcephaly, revealing a new form of laminopathy. The unique nature of the lamin B-associated phenotype highlights different developmental requirements for lamin paralogs and suggests a novel mechanism for primary microcephaly that warrants further investigation.
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 inLMNB1andLMNB2have 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 -helical rod domain, likely disrupting interactions required for higher-order assembly of lamin filaments. Conclusion We identify dominant pathogenic variants inLMNB1andLMNB2as 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.
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