Bradycardia gene identified
Bradycardia gene identified
Milan, Italy - A team of Italian researchers has discovered that bradycardia is associated with a mutation in a gene coding for a cardiac pacemaker channel in a large family . Dr Raffaella Milanesi (University of Milan, Italy) and colleagues report their findings in the January 12, 2006 issue of the New England Journal of Medicine.
Although previous reports of a defective pacemaker channel have been linked with disorders of cardiac rhythm, these either were based on one patient only or described a complex array of rhythm disturbances without clarifying which specific effect was related to the mutation, the researchers note. "We found that sinus bradycardia in members of a large family was associated with a mutation in the gene coding for the pacemaker HCN4 ion channel."
Senior researcher, physiologist Dr Dario DiFrancesco (University of Milan, Italy), told heartwire there are three main implications from this discovery. First, he says, "It is extremely likely that other mutations of this channel are linked to other rhythm disorders." Second, because all the people investigated so far have an autosomal dominant form of the gene, this may have adverse consequences if affected family members, such as cousins, decided to marry and have children, he notes. Finally, this channel is also expressed in the brain, and there's a possibility that other pathologies, such as frontal lobe epilepsy, are linked to mutations in this or other genes, he says.
Closing a gap between basic science and clinical practice
DiFrancesco explained to heartwire that he and his colleagues were screening people with bradycardia when they found one patient with this mutation, in the gene coding for the pacemaker HCN4 ion channel, which is located in the sinoatrial node. DiFrancesco himself—an expert on ion channels—discovered this pacemaker channel (sometimes known as the "funny" channel) while working in Oxford, UK more than 25 years ago.
"We then screened 27 further members of this large Italian family and found that 15 of them were bradycardic." Those affected had markedly lower heart rates than nonaffected members of the family, he says, with average pulses of 52 beats per minute (bpm) compared with around 73 bpm. "Imagine our surprise when we discovered that all 15 of these people had the same bradycardic mutation," he adds. "The bradycardia and the HCN4 gene are so tightly linked that the bradycardia gene is the HCN4 gene. The HCN4 gene is the gene that gives rise to this type of bradycardia."
The pacemaker channels of the sinoatrial node generate spontaneous activity and mediate cyclic-AMP (cAMP)-dependent modulation of the heart rate. The mutation associated with bradycardia is located near the cAMP-binding site. DiFrancesco explains that they found that the mutant channels respond normally to cAMP but are activated at more negative voltages than wild-type channels. These changes mimic those of mild vagal stimulation that slow the heart rate by decreasing the inward diastolic current.
They also discovered that the mutation was autosomal dominant and heterologous—on average, two of the four subunits of the HCN4 protein were affected, with the consequence that these people had a 29% lower heart rate than their nonaffected family members. But if two of these affected people were to marry and have children, and any of them had mutations in all four of the subunits, this would likely not be compatible with life, DiFrancesco said. "If two cousins married, it would be highly risky." The team is now looking into this further using knockout mice, he says.
"We are closing a gap here between a very basic phenomenon and clinical practice," he concludes. "That's rare as far as I am concerned."
Milan, Italy - A team of Italian researchers has discovered that bradycardia is associated with a mutation in a gene coding for a cardiac pacemaker channel in a large family . Dr Raffaella Milanesi (University of Milan, Italy) and colleagues report their findings in the January 12, 2006 issue of the New England Journal of Medicine.
Although previous reports of a defective pacemaker channel have been linked with disorders of cardiac rhythm, these either were based on one patient only or described a complex array of rhythm disturbances without clarifying which specific effect was related to the mutation, the researchers note. "We found that sinus bradycardia in members of a large family was associated with a mutation in the gene coding for the pacemaker HCN4 ion channel."
Senior researcher, physiologist Dr Dario DiFrancesco (University of Milan, Italy), told heartwire there are three main implications from this discovery. First, he says, "It is extremely likely that other mutations of this channel are linked to other rhythm disorders." Second, because all the people investigated so far have an autosomal dominant form of the gene, this may have adverse consequences if affected family members, such as cousins, decided to marry and have children, he notes. Finally, this channel is also expressed in the brain, and there's a possibility that other pathologies, such as frontal lobe epilepsy, are linked to mutations in this or other genes, he says.
Closing a gap between basic science and clinical practice
DiFrancesco explained to heartwire that he and his colleagues were screening people with bradycardia when they found one patient with this mutation, in the gene coding for the pacemaker HCN4 ion channel, which is located in the sinoatrial node. DiFrancesco himself—an expert on ion channels—discovered this pacemaker channel (sometimes known as the "funny" channel) while working in Oxford, UK more than 25 years ago.
"We then screened 27 further members of this large Italian family and found that 15 of them were bradycardic." Those affected had markedly lower heart rates than nonaffected members of the family, he says, with average pulses of 52 beats per minute (bpm) compared with around 73 bpm. "Imagine our surprise when we discovered that all 15 of these people had the same bradycardic mutation," he adds. "The bradycardia and the HCN4 gene are so tightly linked that the bradycardia gene is the HCN4 gene. The HCN4 gene is the gene that gives rise to this type of bradycardia."
The pacemaker channels of the sinoatrial node generate spontaneous activity and mediate cyclic-AMP (cAMP)-dependent modulation of the heart rate. The mutation associated with bradycardia is located near the cAMP-binding site. DiFrancesco explains that they found that the mutant channels respond normally to cAMP but are activated at more negative voltages than wild-type channels. These changes mimic those of mild vagal stimulation that slow the heart rate by decreasing the inward diastolic current.
They also discovered that the mutation was autosomal dominant and heterologous—on average, two of the four subunits of the HCN4 protein were affected, with the consequence that these people had a 29% lower heart rate than their nonaffected family members. But if two of these affected people were to marry and have children, and any of them had mutations in all four of the subunits, this would likely not be compatible with life, DiFrancesco said. "If two cousins married, it would be highly risky." The team is now looking into this further using knockout mice, he says.
"We are closing a gap here between a very basic phenomenon and clinical practice," he concludes. "That's rare as far as I am concerned."
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