A study in Polish patients with cardiomyopathy emphasizes pathogenicity of phospholamban (PLN) mutations at amino acid position 9 and low penetrance of heterozygous null PLN mutations.
BACKGROUND
In humans mutations in the PLN gene, encoding phospholamban - a regulator of sarcoplasmic reticulum calcium ATPase (SERCA), cause cardiomyopathy with prevalence depending on the population. Our purpose was to identify PLN mutations in Polish cardiomyopathy patients.


METHODS
We studied 161 unrelated subjects referred for genetic testing for cardiomyopathies: 135 with dilated cardiomyopathy, 22 with hypertrophic cardiomyopathy and 4 with other cardiomyopathies. In 23 subjects multiple genes were sequenced by next generation sequencing and in all subjects PLN exons were analyzed by Sanger sequencing. Control group included 200 healthy subjects matched with patients for ethnicity, sex and age. Large deletions/insertions were screened by real time polymerase chain reaction.


RESULTS
We detected three different heterozygous mutations in the PLN gene: a novel null c.9_10insA:(p.Val4Serfs*15) variant and two missense variants: c.25C > T:(p.Arg9Cys) and c.26G > T:(p.Arg9Leu). The (p.Val4Serfs*15) variant occurred in the patient with Wolff-Parkinson-White syndrome in whom the diagnosis of cardiomyopathy was not confirmed and his mother who had concentric left ventricular remodeling but normal left ventricular mass and function. We did not detect large deletions/insertions in PLN in cohort studied.


CONCLUSIONS
In Poland, similar to most populations, PLN mutations rarely cause cardiomyopathy. The 9(th) PLN residue is apparently a mutation hot spot whereas a single dose of c.9_10insA, and likely other null PLN mutations, cause the disease only with low penetrance or are not pathogenic.
Laboratory of Molecular Biology, Institute of Cardiology, ul. Alpejska 42, 04-628, Warszawa, Poland. gtruszkowska@ikard.pl.
Grażyna T
GT
Truszkowska
Unit for Screening Studies in Inherited Cardiovascular Diseases, Institute of Cardiology, ul. Alpejska 42, 04-628, Warszawa, Poland. zbilinska@ikard.pl.
Zofia T
ZT
Bilińska
Department of Medical Genetics, Warsaw Medical University, ul. Pawińskiego 3C, 02-106, Warszawa, Poland. samocko@wp.pl.
Joanna
J
Kosińska
Department of Cardiomyopathies, Institute of Cardiology, ul. Alpejska 42, 04-628, Warszawa, Poland. j.sleszycka@ikard.pl.
Justyna
J
Śleszycka
Department of Medical Genetics, Warsaw Medical University, ul. Pawińskiego 3C, 02-106, Warszawa, Poland. mrydzanicz@wum.edu.pl.
Małgorzata
M
Rydzanicz
Department of Heart Failure and Transplantology, Institute of Cardiology, ul. Alpejska 42, 04-628, Warszawa, Poland. msobieszczanska@ikard.pl.
Małgorzata
M
Sobieszczańska-Małek
Laboratory of Molecular Biology, Institute of Cardiology, ul. Alpejska 42, 04-628, Warszawa, Poland. m.fran@wp.pl.
Maria
M
Franaszczyk
Department of Arrhythmia, Institute of Cardiology, ul. Alpejska 42, 04-628, Warszawa, Poland. m.bilinska@ikard.pl.
Maria
M
Bilińska
Department of Immunology, Center for Biostructure Research, Medical University of Warsaw, Warszawa, Poland. stawinski@g.pl.
Piotr
P
Stawiński
Unit for Screening Studies in Inherited Cardiovascular Diseases, Institute of Cardiology, ul. Alpejska 42, 04-628, Warszawa, Poland. e.michalak@ikard.pl.
Ewa
E
Michalak
Department of Interventional Cardiology and Angiology, Institute of Cardiology, ul. Alpejska 42, 04-628, Warszawa, Poland. l.malek@ikard.pl.
Łukasz A
ŁA
Małek
Unit for Screening Studies in Inherited Cardiovascular Diseases, Institute of Cardiology, ul. Alpejska 42, 04-628, Warszawa, Poland. p.chmielewski@ikard.pl.
Przemysław
P
Chmielewski
Unit for Screening Studies in Inherited Cardiovascular Diseases, Institute of Cardiology, ul. Alpejska 42, 04-628, Warszawa, Poland. bfn@ikard.pl.
Bogna
B
Foss-Nieradko
Department of Immunology, Center for Biostructure Research, Medical University of Warsaw, Warszawa, Poland. marcin.m.machnicki@gmail.com.
Marcin M
MM
Machnicki
Department of Immunology, Center for Biostructure Research, Medical University of Warsaw, Warszawa, Poland. tomasz.stoklosa@wum.edu.pl.
Tomasz
T
Stokłosa
Laboratory of Molecular Biology, Institute of Cardiology, ul. Alpejska 42, 04-628, Warszawa, Poland. j.poninska@ikard.pl.
Joanna
J
Ponińska
Department of Arrhythmia, Institute of Cardiology, ul. Alpejska 42, 04-628, Warszawa, Poland. l.szumowski@ikard.pl.
Łukasz
Ł
Szumowski
Department of Cardiomyopathies, Institute of Cardiology, ul. Alpejska 42, 04-628, Warszawa, Poland. j.grzybowski@ikard.pl.
Jacek
J
Grzybowski
Department of Epidemiology, Cardiovascular Diseases Prevention and Promotion of Health, Institute of Cardiology, ul. Niemodlińska 33, 04-635, Warszawa, Poland. j.piwonski@ikard.pl.
Jerzy
J
Piwoński
Department of Epidemiology, Cardiovascular Diseases Prevention and Promotion of Health, Institute of Cardiology, ul. Niemodlińska 33, 04-635, Warszawa, Poland. w.drygas@ikard.pl.
Wojciech
W
Drygas
Department of Heart Failure and Transplantology, Institute of Cardiology, ul. Alpejska 42, 04-628, Warszawa, Poland. t.zielinski@ikard.pl.
Tomasz
T
Zieliński
Department of Medical Genetics, Warsaw Medical University, ul. Pawińskiego 3C, 02-106, Warszawa, Poland. rploski@wp.pl.
Rafał
R
Płoski
D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002135:Calcium-Binding Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D009202:Cardiomyopathies / Q000209:etiology / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D019683:Penetrance; D011044:Poland; D000099211:Phospholamban
D002135:Calcium-Binding Proteins; D000099211:Phospholamban