HGNC Approved Gene Symbol: LMNB2
SNOMEDCT: 1228857005;
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:2,428,166-2,456,959 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.3 | ?Epilepsy, progressive myoclonic, 9 | 616540 | Autosomal recessive | 3 |
| {Lipodystrophy, partial, acquired, susceptibility to} | 608709 | Autosomal dominant | 3 | |
| Microcephaly 27, primary, autosomal dominant | 619180 | Autosomal dominant | 3 |
Tribioli et al. (1987) described a human DNA fragment that is replicated early in S-phase of HL-60 cell DNA. Using this fragment to screen a genomic library, Biamonti et al. (1992) found a clone that contained a 13.7-kb insert which was found to code for several transcripts. Transcription of the insert exhibited a complex pattern and a tissue-specific and proliferation-dependent type of regulation. The data were consistent with 2 tandemly arranged transcription units, the 3-prime end of one separated by the 5-prime end of the other by a sequence of about 600 bp containing an active promoter. Sequencing of the insert led to the identification of 2 genes, one of which encoded a B-type human lamin analogous to mouse lamin B2 (Hoger et al., 1990).
Biamonti et al. (1992) mapped the LMNB2 gene to chromosome 19p13.3 by in situ hybridization.
Biamonti et al. (1992) observed that in synchronized HL-60 cells, the segment of DNA labeled L30E and corresponding to the LMNB2 gene was replicated in the first minute of S-phase. Replication of the lamin gene early in S-phase may reflect a coupling between early replication and transcription of the genes for S-phase-specific proteins such as lamins. Lamin proteins line the inner side of the nuclear envelope with a meshwork of filamentous structures and are thought to play a role in nuclear stability, chromatin structure, and gene expression.
Living organisms regulate the rate of DNA replication by modulating the activation of replication origins. In eukaryotes, every chromosome is composed of many tandemly organized replicons, which are activated at different times of the S phase and are characterized by an origin from which 2 oppositely moving semiconservative forks issue. Identification of replication origins in animal systems has proved very difficult. Giacca et al. (1994) developed a highly sensitive procedure for the identification of the origin of bidirectional DNA synthesis in single-copy replicons of mammalian cells. The procedure was used to map the start site of DNA replication in a 13.7-kb region of human chromosome 19 coding for lamin B2, which is replicated immediately after the onset of S phase in cultured HL-60 cells. Within this region, DNA replication initiates in a 474-bp area corresponding to the 3-prime noncoding end of the LMNB2 gene and the nontranscribed spacer between this gene and the 5-prime end of another highly transcribed one. The downstream gene, referred to by Giacca et al. (1994) as ppv1, was transcribed in the same direction and was later found to be the TIMM13 gene (607383).
Kim et al. (2011) found that mouse embryonic stem cells do not need any lamins for self-renewal and pluripotency. Although genomewide lamin-B binding profiles correlate with reduced gene expression, such binding is not directly required for gene silencing in embryonic stem cells or trophectoderm cells. However, B-type lamins are required for proper organogenesis. Defects in spindle orientation in neural progenitor cells and migration of neurons probably cause brain disorganizations found in lamin-B-null mice. Kim et al. (2011) concluded that their studies not only disprove several prevailing views of lamin-Bs but also establish a foundation for redefining the function of the nuclear lamina in the context of tissue building and homeostasis.
Hegele et al. (2006) stated that the LMNB2 gene contains 12 exons.
Acquired Partial Lipodystrophy
In a search for disease-associated mutations in acquired partial lipodystrophy (APLD; 608709), Hegele et al. (2006) interrogated the coding regions of the LMNB2 gene in 9 unrelated APL patients whose conditions were diagnosed by established criteria. In 4 patients, Hegele et al. (2006) found 3 novel mutations in LMNB2: IVS1AS-6G-T (150341.0001), R215Q (150341.0002), and A407T (150341.0003). These novel heterozygous mutations were the first reported for LMNB2 and the first reported among patients with APL. The R215Q variant was observed in 3 of 330 white controls and in 1 of 375 East Indian controls. Hegele et al. (2006) noted that the disorder does not show classic mendelian inheritance and suggested that susceptibility to the disease may be conferred by several alleles.
Progressive Myoclonic Epilepsy 9
In 2 sisters, born of consanguineous Palestinian Arab parents, with progressive myoclonic epilepsy-9 (EPM9; 616540), Damiano et al. (2015) identified a homozygous missense mutation in the LMNB2 gene (H157Y; 150341.0005). The mutation was found by a combination of homozygosity mapping and candidate gene sequencing as well as whole-exome sequencing. Each unaffected parent was heterozygous for the mutation. In vitro functional expression assays showed that the mutant protein organized into irregularly connected network-type structures and lacked higher order arrangement compared to wildtype. The findings were consistent with a disruption of proper fibrillar assembly and suggested that disruption of the organization of the nuclear lamina in neurons, perhaps through abnormal neuronal migration, caused the disorder. Direct sequencing of the LMNB2 gene in 87 additional cases with a similar disorder did not identify any mutations.
Autosomal Dominant Primary Microcephaly 27
In 6 unrelated patients (P4-P8, P12) with autosomal dominant primary microcephaly-27 (MCPH27; 619180), Parry et al. (2021) identified heterozygous mutations in the LMNB2 gene (E398K, 150341.0006 and N54H, 150341.0007). Five patients carried the recurrent E398K mutation. The mutations, which were found by exome sequencing, occurred de novo in most patients, but in 1 was inherited from an unaffected mosaic mother. The mutations were not present in the gnomAD database. The location of the mutations predicted interference with dimer or filament assembly, and in vitro functional expression studies in cells transfected with the mutant proteins showed that both caused abnormal LMNB nuclear aggregates and an altered nuclear shape. Parry et al. (2021) postulated that the mutations may alter the properties of lamin filaments, resulting in fragile nuclei that are susceptible to the mechanical stresses of nuclear and neuronal migration, leading to increased cell death during brain development.
In a patient with acquired partial lipodystrophy (APLD; 608709), Hegele et al. (2006) identified a splice acceptor site mutation on one allele in the LMNB2 gene: IVS1AS-6C-T. The patient, 46 years old at the time of report, had onset of fat loss at the age of about 17 years and a diagnosis of diabetes at the age of 27 years. The variant was not seen in 1,100 multiethnic controls. Hegele et al. (2006) noted that the disorder does not show classic mendelian inheritance and suggested that susceptibility to the disease may be conferred by several alleles.
In 2 unrelated patients with acquired partial lipodystrophy (APLD; 608709), Hegele et al. (2006) identified a heterozygous 643G-A transition in exon 5 of the LMNB2 gene, resulting in an arg215-to-gln (R215Q) substitution. One patient was 64 years old at the age of study. Loss of fat had begun at the age of about 16 years with diabetes at the age of 37 years. Loss of fat was symmetrical, involving the upper body and extending to the upper thighs. Type IV dyslipidemia, hypertension, polycystic ovary disease, and dermatomyositis were present in this patient. The patient also had hepatosplenomegaly, coronary artery disease, osteoporosis, and alopecia. A second patient, age 40, had loss of fat beginning at the age of about 5 years; diabetes began at the age of 19 years. Fat loss extended over the upper body to the level of the knees. Type V dyslipidemia and eruptive xanthomata of the elbows and knees were present. Retinal involvement was described as well as bilateral carpal tunnel syndrome. The R215Q variant was observed in 3 of 330 white controls and in 1 of 375 East Indian controls. Hegele et al. (2006) noted that the disorder does not show classic mendelian inheritance and suggested that susceptibility to the disease may be conferred by several alleles.
In a 59-year-old patient with acquired partial lipodystrophy (APLD; 608709), Hegele et al. (2006) identified a heterozygous 1218G-A transition in the LMNB2 gene, resulting in an ala407-to-thr (A407T) substitution. The patient had onset of fat loss at approximately 17 years of age and had no diabetes. Fat loss involved the upper body symmetrically to the upper thighs. Type IV dyslipidemia and hypertension were present. The patient had had a cerebral infarct at the age of 30 years. The variant was not seen in 1,100 multiethnic controls. Hegele et al. (2006) noted that the disorder does not show classic mendelian inheritance and suggested that susceptibility to the disease may be conferred by several alleles.
In a 26-year-old Chinese woman with acquired partial lipodystrophy (APLD; 608709), Gao et al. (2012) identified a de novo heterozygous c.694T-C transition in exon 5 of the LMNB2 gene, resulting in a tyr232-to-his (Y232H) substitution at a conserved residue in the rod domain. Functional studies of the variant were not performed. The patient had symmetric loss of subcutaneous fat from the face and upper part of the body beginning around age 14. As a young adult, she had fatty liver and mild metabolic disorder with increased insulin. She also developed early menopause with decreasing estrogen levels. There was no family history of a similar disorder.
In 2 sisters, born of consanguineous Palestinian Arab parents, with progressive myoclonic epilepsy-9 (EPM9; 616540), Damiano et al. (2015) identified a homozygous c.469C-T transition (c.469C-T, NM_032737) in the LMNB2 gene, resulting in a his157-to-tyr (H157Y) substitution at a highly conserved residue in the coiled-coil domain. The mutation, which was found by a combination of homozygosity mapping and candidate gene sequencing as well as whole-exome sequencing, was not found in the 1000 Genomes Project, Exome Variant Server, or ExAc databases or in 386 controls. Each unaffected parent was heterozygous for the mutation. In vitro functional expression assays showed that the mutant protein organized into irregularly connected network-type structures and lacked higher order arrangement compared to wildtype. The findings were consistent with a disruption of proper fibrillar assembly and suggested that disruption of the organization of the nuclear lamina in neurons, perhaps through abnormal neuronal migration, caused the disorder.
In 5 unrelated patients (P4-P7, P12) with autosomal dominant primary microcephaly-27 (MCPH27; 619180), Parry et al. (2021) identified a recurrent heterozygous c.1192G-A transition (c.1192G-A, NM_032737.4) in the LMNB2 gene, resulting in a glu398-to-lys (E398K) substitution at a conserved residue at the intradimer interface of coil 2B. The mutation, which was found by exome sequencing, was established to occur de novo in 3 of the patients, whereas it was inherited from an unaffected mosaic mother in the fourth patient. Parental DNA was not available for the remaining patient. The mutation was not present in the gnomAD database. The location of the mutation predicted interference with dimer or filament assembly, and in vitro functional expression studies in cells transfected with the mutant protein showed that it caused abnormal LMNB nuclear aggregates and an altered nuclear shape. The authors postulated a dominant-negative effect.
In a 12-year-old girl (P8) with autosomal dominant primary microcephaly-27 (MCPH27; 619180), Parry et al. (2021) identified a de novo heterozygous c.160A-C transversion (c.160A-C, NM_032737.4) in the LMNB2 gene, resulting in an asn54-to-his (N54H) substitution at a conserved residue at the intradimer interface of coil 1A. The mutation, which was found by exome sequencing, was not present in the gnomAD database. The location of the mutation predicted interference with dimer or filament assembly, and in vitro functional expression studies in cells transfected with the mutant protein showed that it caused abnormal LMNB nuclear aggregates and an altered nuclear shape. The authors postulated a dominant-negative effect.
Biamonti, G., Giacca, M., Perini, G., Contreas, G., Zentilin, L., Weighardt, F., Guerra, M., Della Valle, G., Saccone, S., Riva, S., Falaschi, A. The gene for a novel human lamin maps at a highly transcribed locus of chromosome 19 which replicates at the onset of S-phase. Molec. Cell. Biol. 12: 3499-3506, 1992. [PubMed: 1630457] [Full Text: https://doi.org/10.1128/mcb.12.8.3499-3506.1992]
Damiano, J. A., Afawi, Z., Bahlo, M., Mauermann, M., Misk, A., Arsov, T., Oliver, K. L., Dahl, H.-H. M., Shearer, A. E., Smith, R. J. H., Hall, N. E., Mahmood, K., Leventer, R. J., Scheffer, I. E., Muona, M., Lehesjoki, A.-E., Korczyn, A. D., Herrmann, H., Berkovic, S. F., Hildebrand, M. S. Mutation of the nuclear lamin gene LMNB2 in progressive myoclonus epilepsy with early ataxia. Hum. Molec. Genet. 24: 4483-4490, 2015. [PubMed: 25954030] [Full Text: https://doi.org/10.1093/hmg/ddv171]
Gao, J., Li, Y., Fu, X., Luo, X. A Chinese patient with acquired partial lipodystrophy caused by a novel mutation with LMNB2 gene. J. Pediat. Endocr. Metab. 25: 375-377, 2012. [PubMed: 22768673] [Full Text: https://doi.org/10.1515/jpem-2012-0007]
Giacca, M., Zentilin, L., Norio, P., Diviacco, S., Dimitrova, D., Contreas, G., Biamonti, G., Perini, G., Weighardt, F., Riva, S., Falaschi, A. Fine mapping of a replication origin of human DNA. Proc. Nat. Acad. Sci. 91: 7119-7123, 1994. [PubMed: 8041756] [Full Text: https://doi.org/10.1073/pnas.91.15.7119]
Hegele, R. A., Cao, H., Liu, D. M., Costain, G. A., Charlton-Menys, V., Rodger, N. W., Durrington, P. N. Sequencing of the reannotated LMNB2 gene reveals novel mutations in patients with acquired partial lipodystrophy. Am. J. Hum. Genet. 79: 383-389, 2006. [PubMed: 16826530] [Full Text: https://doi.org/10.1086/505885]
Hegele, R. A., Yuen, J., Cao, H. Single-nucleotide polymorphisms of the nuclear lamina proteome. J. Hum. Genet. 46: 351-354, 2001. [PubMed: 11393540] [Full Text: https://doi.org/10.1007/s100380170072]
Hoger, T. H., Zatloukal, K., Waizenegger, I., Krohne, G. Characterization of a second highly conserved B-type lamin present in cells previously thought to contain only a single B-type lamin. Chromosoma 99: 379-390, 1990. Note: Erratum: Chromosoma 100: 67-69, 1990. [PubMed: 2102682] [Full Text: https://doi.org/10.1007/BF01726689]
Kim, Y., Sharov, A. A., McDole, K., Cheng, M., Hao, H., Fan, C.-M., Gaiano, N., Ko, M. S. H., Zheng, Y. Mouse B-type lamins are required for proper organogenesis but not by embryonic stem cells. Science 334: 1706-1710, 2011. [PubMed: 22116031] [Full Text: https://doi.org/10.1126/science.1211222]
Parry, D. A., Martin, C.-A., Greene, P., Marsh, J. A., Genomics England Research Consortium, Blyth, M., Cox, H., Donnelly, D., Greenhalgh, L., Greville-Heygate, S., Harrison, V., Lachlan, K., McKenna, C., Quigley, A. J., Rea, G., Robertson, L., Suri, M., Jackson, A. P. Heterozygous lamin B1 and lamin B2 variants cause primary microcephaly and define a novel laminopathy. Genet. Med. 23: 408-414, 2021. [PubMed: 33033404] [Full Text: https://doi.org/10.1038/s41436-020-00980-3]
Tribioli, C., Biamonti, G., Giacca, M., Colonna, M., Riva, S., Falaschi, A. Characterization of human DNA sequences synthesized at the onset of S-phase. Nucleic Acids Res. 15: 10211-10232, 1987. [PubMed: 2827117] [Full Text: https://doi.org/10.1093/nar/15.24.10211]