Supplemental Table 1. Conservation of amino acids at positions 72, 190, 382 and 644 of LMNA among orthologues from different species.
Protein sequences were accessed on Ensembl (http://www.ensembl.org/) and aligned using CLUSTAL W multiple sequence alignment
(http://www.ebi.ac.uk/Tools/msa/clustalw2/).
Species (Ensembl peptide ID)
R72C
↓
R190W
↓
G382V
↓
R644C
↓
Human (ENSP00000357283)
……….EVVSREVSGI……
………EMLRRVDAE……
………KLLEGEEER……
………NLVTRSYLL……
Gorilla (ENSGGOP00000000800)
……….EVVSREVSGI……
…….EMLRRVDAE……
………KLLEGEEER……
………NLVTRSYLL……
Chimpanzee (ENSPTRP00000002446)
……….EVVSREVSGI……
………HMLRRVDAE……
………KLLEGEEER……
………NLVTRSYLL……
Pig (ENSSSCP00000006923)
……….EVVSREVSGI……
……….EMLRRVDAE……
………KLLEGEEER……
………NLVTRSYLL……
Cow (ENSBTAP00000023373)
….…….EVVSREVSGI……
……….EMLRRVDAE……
………KLLEGEEER……
………SLVTRSYLL……
Horse (ENSECAP00000009322)
……….EVVSREVSGI……
……….EMLRRVDAE……
………KLLEGEEER……
………NLVTRSYLL……
Dog (ENSCAFP00000024801)
……….EVVSREVSGI……
……….EMLRRVDAE……
………KLLEGEEER……
………SLVTRSYLL……
Chicken (ENSGALP00000009801)
………AGSGRELGCL……
……….EMLRRVDLE……
……...KMLEGEEQR……
Rat (ENSRNOP00000026705)
……….EVVSREVSGI……
……….EMLRRVDAE……
………KLLEGEEER……
………NLVTRSYLL……
Guinea pig (ENSCPOP00000015745)
sequence not determined
sequence not determined
………KLLEGEEER……
………NLVTRSYLL……
Mouse (ENSMUSP00000029699)
…….EVVSREVSGI……
……….EMLRRVDAE……
………KLLEGEEER……
………NLVTRSYLL……
Zebrafish (ENSDARP00000113049)
…….ETEISRELSGM……
……....EMLRRVDAE……
………KLLEGEEER……
………AFVSPSHFI……
Fruitfly (FBpp0086641)
…….DTVNRETSNL……
…….….ETLARVDLE……
………KLLCGEERR……
*shorter orthologue – no alignment
-------------- *
-------------- *
Supplemental Table 2. In silico prediction models for the LMNA variants found in our ARVC cohort.
LMNA Sequence
Variant
Coding effect
UMD-LMNA mutation
database
Grantham
score
PolyPhen-2 prediction
(score)
SIFT prediction
(score)
c.214C>T
c.586C>T
c.1145G>T
c.1930C>T
R72C
R190W
G382V
R644C
Novel
180
Known pathogenic
variant
101
Novel
109
Known pathogenic
variant
180
Probably damaging
(1.00)
Not tolerated.
Probably damaging
(1.00)
Not tolerated.
Possibly damaging
(0.933)
Not tolerated.
Probably damaging
(0.997)
Not tolerated.
Affects protein function (0.00)
Affects protein function (0.00)
Affects protein function (0.01)
Affects protein function (0.00)
The UMD-LMNA mutation database (http://www.umd.be/LMNA/) was used to identify previously reported sequence variants. The likelihood
of pathogenic effect of LMNA sequence variants was determined by three in silico prediction methods: The Grantham score, PolyPhen-2, and
SIFT. 1-3
Legend to Supplemental Figures
Supplemental Figure 1: Panoramic view of the endomyocardial biopsy from patient A.
Supplemental Figure 2: Gross cardiac pathology from patient D: right ventricular apex showing fatty replacement and b) longitudinal section
through the inferior atrioventricular junction showing near total fatty replacement.
Supplemental Figure 3: His-bundle section from patient D showing mild fibrosis (Elastic van Gieson staining, original magnification x200)
Supplemental Figure 1
Supplemental Figure 2
Supplemental Figure 3
Supplemental References
1. Grantham R. Amino acid difference formula to help explain protein evolution. Science 1974;185:862-4.
2. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR. A method and server for predicting
damaging missense mutations. Nat Methods. 2010;7:248-9.
3. Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat
Protoc. 2009;4:1073-81.