A novel ‘splice site’ HCN4 Gene mutation, c.1737 + 1 G > T, causes familial bradycardia, reduced heart rate response, impaired chronotropic competence and increased short-term heart rate variability
| Autor: | Tamás Forster, László Rudas, László Sághy, András Varró, Beáta Csányi, Márta Széll, Kornél Kákonyi, István Nagy, Balázs Ördög, Lidia Hategan, Orsolya Kiss, Róbert Sepp, Zoltán Hegedűs, Andrea Orosz, Annamária Tringer |
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| Rok vydání: | 2017 |
| Předmět: |
Adult
Male 0301 basic medicine Bradycardia Chronotropic Gene isoform medicine.medical_specialty Potassium Channels Adolescent Muscle Proteins Disease 030204 cardiovascular system & hematology medicine.disease_cause Sick sinus syndrome Electrocardiography Young Adult 03 medical and health sciences 0302 clinical medicine Heart Rate Internal medicine Heart rate Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels Humans Medicine Heart rate variability Child Sick Sinus Syndrome Mutation business.industry Middle Aged medicine.disease Pedigree 030104 developmental biology Endocrinology Cardiology Female RNA Splice Sites medicine.symptom Cardiology and Cardiovascular Medicine business |
| Zdroj: | International Journal of Cardiology. 241:364-372 |
| ISSN: | 0167-5273 |
| Popis: | The most important molecular determinant of heart rate regulation in sino-atrial pacemaker cells includes hyperpolarization-activated, cyclic nucleotide-gated ion channels, the major isoform of which is encoded by the HCN4 gene. Mutations affecting the HCN4 gene are associated primarily with sick sinus syndrome.A novel c.1737+1 GT 'splice-site' HCN4 mutation was identified in a large family with familial bradycardia which co-segregated with the disease providing a two-point LOD score of 4.87. Twelve out of the 22 investigated family members [4 males, 8 females average age 36 (SD 6) years] were considered as clinically affected (heart rate60/min on resting ECG). Minimum [36 (SD 7) vs. 47 (SD 5) bpm, p=0.0087) and average heart rates [62 (SD 8) vs. 73 (SD 8) bpm, p=0.0168) were significantly lower in carriers on 24-hour Holter recordings. Under maximum exercise test carriers achieved significantly lower heart rates than non-carrier family members, and percent heart rate reserve and percent corrected heart rate reserve were significantly lower in carriers. Applying rigorous criteria for chronotropic incompetence a higher number of carriers exhibited chronotropic incompetence. Parameters, characterizing short-term variability of heart rate (i.e. rMSSD and pNN50%) were increased in carrier family members, even after normalization for heart rate, in the 24-hour ECG recordings with the same relative increase in 5-minute recordings.The identified novel 'splice site' HCN4 gene mutation, c.1737+1 GT, causes familial bradycardia and leads to reduced heart rate response, impaired chronotropic competence and increased short-term heart rate variability in the mutation carriers. |
| Databáze: | OpenAIRE |
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