Tohoku J. Exp. Med., 2009, 218(4)

Lamin A/C Gene Mutations in Familial Cardiomyopathy with Advanced Atrioventricular Block and Arrhythmia

AKIKO SAGA,¹ AKIHIKO KARIBE,¹ JUN OTOMO,² KAORU IWABUCHI,³ TOSHIAKI TAKAHASHI,⁴ HIROYUKI KANNO,⁵ JUNICHI KIKUCHI,⁶ MITSUMASA KEITOKU,² TSUYOSHI SHINOZAKI⁷ and HIROAKI SHIMOKAWA¹

¹Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
²Department of Cardiology, Tohoku Kosai Hospital, Sendai, Japan
³Department of Cardiology, Osaki City Hospital, Osaki, Japan
⁴Second Department of Internal Medicine, Hiraka General Hospital, Yokote, Japan
⁵Department of Cardiology, Katta General Hospital, Shiroishi, Japan
⁶Second Department of Internal Medicine, Towada Municipal Central Hospital, Towada, Japan
⁷Department of Cardiology, Sendai Medical Center, Sendai, Japan

Lamin A and C proteins, encoded by the lamin A/C gene (LMNA), are inner nuclear membrane proteins predominantly expressed in terminally differentiated cells. Mutations in LMNA can cause various forms of cardiomyopathy with arrhythmia in an autosomal dominant manner. We collected and evaluated the clinical characteristics of unclassified familial cardiomyopathy with advanced AV block and sporadic cases with advanced AV block. Mutation in LMNA was directly screened using the cycle sequencing method in 5 probands of the familial cardiomyopathy and 60 sporadic cases with advanced AV block. In four of the five familial cases (80%), we identified four distinct mutations: two protein-truncation mutations, R225X and 815_818delinsCCAGAC, and two missense mutations, Y259H and R166P. No sporadic cases carried LMNA mutation. Left ventricular end-diastolic diameter (LVEDD) was slightly enlarged in LMNA mutant carriers (123.5 ± 9.5%) as well as in non-carriers (125.1 ± 13.3%), while left ventricular fractional shortening (LVFS) was preserved in LMNA mutant carriers (32.3 ± 4.8%) and non-carriers (37.6 ± 6.8%). In LMNA mutation carriers, the average age at onset of advanced AV block is significantly lower than that in non-carriers (43.7 ± 9.5 vs. 65.3 ± 13 yr., p < 0.01). Ventricular tachycardia, sudden death, and poor prognosis were observed in LMNA mutation carriers. LMNA mutation could cause familial cardiomyopathy with insignificant LV remodeling, early-age onset of advanced AV block, and lethal ventricular arrhythmia. Screening of LMNA mutation might be beneficial for risk stratification and clinical management of this type of unclassified familial cardiomyopathy.

Keywords —— Cardiomyopathy; atrioventricular block; ventricular tachycardia; sudden death; molecular genetics.

© 2009 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2009, 218, 309-316

Correspondence: Akihiko Karibe, Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.

e-mail: akaribe@mail.tains.tohoku.ac.jp