Rare BANF1 Alleles and Relatively Frequent EMD Alleles Including ‘Healthy Lipid’ Emerin p.D149H in the ExAC Cohort

Abstract

Emerin ( EMD ) and barrier to autointegration factor 1 ( BANF1 ) each bind A-type lamins ( LMNA ) as fundamental components of nuclear lamina structure. Mutations in LMNA , EMD and BANF1 are genetically linked to many tissue-specific disorders including Emery-Dreifuss muscular dystrophy and cardiomyopathy ( LMNA , EMD ), lipodystrophy, insulin resistance and type 2 diabetes ( LMNA ) and progeria ( LMNA , BANF1 ). To explore human genetic variation in these genes, we analyzed EMD and BANF1 alleles in the Exome Aggregation Consortium (ExAC) cohort of 60,706 unrelated individuals. We identified 13 rare heterozygous BANF1 missense variants (p.T2S, p.H7Y, p.D9N, p.S22R, p.G25E, p.D55N, p.D57Y, p.L63P, p.N70T, p.K72R, p.R75W, p.R75Q, p.G79R), and one homozygous variant (p.D9H). Several variants are known (p.G25E) or predicted (e.g., p.D9H, p.D9N, p.L63P) to perturb BANF1 and warrant further study. Analysis of EMD revealed two previously identified variants associated with adult-onset cardiomyopathy (p.K37del, p.E35K) and one deemed ‘benign’ in an Emery-Dreifuss patient (p.D149H). Interestingly p.D149H was the most frequent emerin variant in ExAC, identified in 58 individuals (overall allele frequency 0.06645%), of whom 55 were East Asian (allele frequency 0.8297%). Furthermore, p.D149H associated with four ‘healthy’ traits: reduced triglycerides (-0.336; p = 0.0368), reduced waist circumference (-0.321; p = 0.0486), reduced cholesterol ( - 0.572; p = 0.000346) and reduced LDL cholesterol (-0.599; p = 0.000272). These traits are distinct from LMNA -associated metabolic disorders and provide the first insight that emerin influences metabolism. We also identified one novel in-frame deletion (p.F39del) and 62 novel emerin missense variants, many of which were relatively frequent and potentially disruptive including p.N91S and p.S143F (∼0.041% and ∼0.034% of non-Finnish Europeans, respectively), p.G156S (∼0.39% of Africans), p.R204G (∼0.18% of Latinx), p.R207P (∼0.08% of South Asians) and p.R221L (∼0.15% of Latinx). Many novel BANF1 variants are predicted to disrupt dimerization or binding to DNA, histones, emerin or A-type lamins. Many novel emerin variants are predicted to disrupt emerin filament dynamics or binding to BANF1, HDAC3, A-type lamins or other partners. These new human variants provide a foundational resource for future studies to test the molecular mechanisms of BANF1 and emerin function, and to understand the link between emerin variant p.D149H and a ‘healthy’ lipid profile.

Novel missense alleles of SIGMAR1 as tools to understand emerin-dependent gene silencing in response to cocaine

“…Emerin has an N-terminal LEM-domain and large intrinsically disordered region, both of which are nucleoplasmic, followed by a TMD and short lumenal domain. 26,34 Thus, emerin has the potential to bind Sigma1R in either orientation, and to be affected by specific variant(s), if emerin is the direct partner as modeled in Figure 5. If emerin is not the direct partner, the same logic will apply to other candidates not depicted in Figure 5 (e.g.…”

“…Our recent analyses of LMNA, EMD, and BANF1 variants in ExAC revealed novel variants and unexpectedly high frequencies of disease-causing dominant variants in LMNA, as well as novel association with psychiatric disease (LMNA variant p.K108E) or type 2 diabetes (LMNA variant p.G602S) 25 and novel association with healthy metabolic traits (EMD variant p.D149H). 26 Here we report the identification of novel SIGMAR1 missense variants in ExAC, two of which were widespread and common with allele frequencies of 2-3% or >18% in specific ethnic groups. These and other variants of interest are discussed in relation to the atomic structure of the full-length Sigma1R trimer 27 and still-unresolved questions about its membrane topology and orientation at the INM.…”

<p>Expression and Prognostic Significance of BANF1 in Triple-Negative Breast Cancer</p>

“…Patients diagnosed with TNBC after chemotherapy have poorer outcomes than patients with other breast cancer subtypes. 2 Barrier-to-autointegration factor 1 (BANF1) is a highly conserved DNA-binding protein that forms homodimers and has a variety of functions associated with the maintenance of the intact cellular genome, which regulates gene expression, participates in the formation of karyotin structures and is associated with cell mitosis, 3 indicating its vital role in the process of malignant transformation of cells. The present study was designed to investigate Correspondence: Genhao Zhang Blood Transfusion, Zhengzhou University First Affiliated Hospital, Zhengzhou, People's Republic of China Tel +86 158 3816 5680 Email wangshuya617@bjmu.edu.cn the expression profile of BANF1 in TNBC and its relationship with clinical-pathological characteristics and to explore the relationship between BANF1 and the prognosis of patients with TNBC by survival analysis.…”

DataSheet1.PDF

“…In order to identify rare Banf1 human variants, we first utilised the Genome Aggregation database (gnomAD) v3.1 short variant data set, containing 76,156 genomes from unrelated individuals. In addition to the 13 missense variants previously identified using the ExAC server (Dharmaraj et al, 2019), this analysis found an additional 10 Banf1 variants (Figure 1A). From these 23 Banf1 human variants we selected 7 variants that were present on both the ExAC server (Dharmaraj et al, 2019) and the GnomAD server (Figures 1A,B).…”

“…Given the importance of Banf1 in maintaining cellular homeostasis, it is crucial we increase our understanding of the association between Banf1 human variants and their structure and function in human cells. Previously, a study investigated several Banf1 variants identified from the Exome Aggregation Consortium (ExAC) cohort of 60,706 unrelated individuals and speculated that several Banf1 variants might impact the dsDNA binding affinity (Lek et al, 2016;Dharmaraj et al, 2019). Here, we extend this previous study and investigate the effect of rare human variants on Banf1 structure and function, using molecular modelling, biophysical and cell-based analyses.…”