• 0
    Haplo
    Score
  • 3
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
LMNB1 (HGNC:6637) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
lamin B1
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
No previous names found
Alias symbols
No aliases found
%HI
11.52(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.55(Read more about gnomAD pLI score)
LOEUF
0.41(Read more about gnomAD LOEUF score)
Cytoband
5q23.2
Genomic Coordinates
GRCh37/hg19: chr5:126112315-126172712 NCBI Ensembl UCSC
GRCh38/hg38: chr5:126776623-126837020 NCBI Ensembl UCSC
MANE Select Transcript
NM_005573.4 ENST00000261366.10 (Read more about MANE Select)
Function
Lamins are components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane, which is thought to provide a framework for the nuclear envelope and may also interact with chromatin. {ECO:0000269|PubMed:28716252, ECO:0000269|PubMed:32910914}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-35057
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
No Evidence for Haploinsufficiency (0)
Triplosensitivity:
Sufficient Evidence for Triplosensitivity (3)
Last Evaluated:
10/25/2023

Haploinsufficiency (HI) Score Details

HI Score:
0
HI Evidence Strength:
No Evidence for Haploinsufficiency (Disclaimer)

Triplosensitivity (TS) Score Details

TS Score:
3
TS Evidence Strength:
Sufficient Evidence for Triplosensitivity (Disclaimer)
TS Disease:
  • adult-onset autosomal dominant demyelinating leukodystrophy Monarch
TS Published Evidence:
  • PUBMED: 16951681
    Padiath, et al. (2006) utilized multiple methods to identify and characterize a LMNB1 duplication in four families with adult onset autosomal dominant demyelinating leukodystrophy (ADLD) (clinical features previously described see PMIDs: 10749986, 8958750). After identifying the duplication breakpoints in the probands, junction PCR analysis was used "to confirm that the duplication co-segregated with the disease phenotype in kindreds 2685, 4233, and 50069." Of note, the duplications ranged in size from about 150 kb to 341 kb, but all fully encompassed the LMNB1 gene and partially included the MARCH3 gene to varying degrees. Although MARCH3 was partially duplicated in all kindreds, RNA analysis of MARCH3 from brain tissue showed no difference between affected individuals and controls. In LMNB1 (RNA and protein) was shown to be overexpressed in the brain tissue of affected individuals (for which tissue was available) compared to controls. Additionally, ectopic expression of human LMNB1 in fruit fly eyes resulted in disrupted eye morphology, loss of pigmentation or lethality.
  • PUBMED: 23649844
    Giorgio, et al. (2013) include LMNB1 breakpoint analysis for 20 families with ADLD and propose a 72 kb region (GRCh37 chr5:126,102,443 - 126,174,517) as the minimal critical duplicated region necessary for disease. Of the 20 families included in this study, 9 were included in prior publications with segregation analysis available for 4 multi-generational families (PMIDs with segregation: 19001169, 19151023, 21225301, 21909802; without segregation: 20719577, 22287014). Of the 11 additional families new to this study, all but 2 include part of MARCH3. Of note, the duplications in families BR1, A6, A7, and K2-3 were more complex and are not scored for this curation (BR1 has an inverted duplication that includes additional genes proximal to LMNB1; A6, A7, and K2-3 harbor a tandem duplication with and intervening triplication of intron 3 of MARCH3). While haplotype analysis was performed, insufficient information was provided to deduce whether the duplications co-segregated with disease in the newly described families. Additional analysis of a subset of samples confirmed increased LMNB1 mRNA and protein expression in patient cells compared to controls.
  • PUBMED: 28769756
    Dai, et al. (2017) identified an LMNB1 duplication in a 54 year old Chinese male with clinical features and family history consistent with ADLD. Of note, MLPA was used to characterize the duplication therefore the extent of the duplication is unknown. Additional prior NGS testing for 54 genes association with autosomal dominant cortical infarcted cerebral artery disease was negative. The authors confirmed the presence of the duplication in his affected brother and absence of the duplication in his unaffected sister.
  • PUBMED: 30697589
    Mezaki, et al. (2018) identified LMNB1 duplications ranging in size from 153kb to 221kb in 3 families with ADLD. All three duplications fully encompassed the LMNB1 gene and a portion of the MARCH3 gene to varying degrees. Two of the three probands had a family history consistent with ADLD but only one family had genetic analysis from another family member demonstrating co-segregation of the duplication with disease.
TS Evidence Comments:
Whole gene duplications leading to overexpression of LMNB1 are associated with adult onset autosomal dominant demyelinating leukodystrophy (ADLD). Typically, ADLD onset occurs in the fourth to fifth decade of life with autonomic dysfunction (may include bladder dysfunction, constipation, postural hypotension, erectile dysfunction, and occasionally impaired sweating) as the first presenting feature. Motor and cerebellar impairment leading to spasticity, ataxia, and tremor become apparent with disease progression. Nearly all duplications described in the literature to date appear to include a portion of the MARCH3 gene, but there is no evidence supporting a role for MARCH3 in disease causality. Additionally, at least 2 families with ADLD have been reported with duplications that do not involve MARCH3. Multiple experimental analyses and animal models have also been generated that demonstrate a deleterious effect of LMNB1 overexpression, most notably mouse models demonstrating over-expression of LMNB1 lead to demyelination and age-dependent motor dysfunction (summarized in GeneReviews and PMID: 37450245). Additional more recent publications describing ADLD families with duplications of LMNB1 are available, but do not provide details regarding the size and content of the duplication (PMIDs: 23681646, 34447008, 35419641). In addition to whole gene duplication of LMNB1, several recent publications have identified deletions upstream of LMNB1 as causative for ADLD (PMIDs: 25701871, 30697589, 30842973, 35247231). Most reported patients appear to have increased expression of LMNB1 and Giorgio, et al. (2015) provide data suggesting that these deletions remove a nearby LMNB1 enhancer and bring a different enhancer closer to the LMNB1 promoter (PMID: 25701871).

Genomic View

Select assembly: (NC_000005.9) (NC_000005.10)