SNP association and sequence analysis of the NOS1AP gene in SIDS

Osawa, Motoki; Kimura, Ryousuke; Hasegawa, Iwao; Mukasa, Nahoko; Satoh, Fumiko

doi:10.1016/j.legalmed.2009.01.065

Cited by 19 publications

(13 citation statements)

References 9 publications

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“…Most importantly, these findings strongly suggested that nNOS plays an important role in modulating the late I Na underlying sodium channel-mediated LQTS and sudden unexplained cardiac death. Notably, the previously reported influences of common variation involving the neuronal nitric oxide synthase adaptor protein (NOS1AP, an nNOS regulator) on QT interval duration37-41 and most recently the observed association of NOS1AP genetic variants with sudden cardiac death42 as well as SIDS43 have confirmed the important role of nNOS in LQTS-related disorders. Thus, the deeper association of nNOS complex-related proteins (for example nNOS regulators like PMCA4b) as potential candidate genes for LQTS and sudden cardiac death deserves further study.…”

Section: Discussionmentioning

confidence: 76%

α1-Syntrophin Mutations Identified in Sudden Infant Death Syndrome Cause an Increase in Late Cardiac Sodium Current

Cheng

Norstrand

Medeiros-Domingo

et al. 2009

Circ: Arrhythmia and Electrophysiology

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Background-Sudden infant death syndrome (SIDS) is a leading cause of death during the first 6 months after birth. About 5% to 10% of SIDS may stem from cardiac channelopathies such as long-QT syndrome. We recently implicated mutations in ␣1-syntrophin (SNTA1) as a novel cause of long-QT syndrome, whereby mutant SNTA1 released inhibition of associated neuronal nitric oxide synthase by the plasma membrane Ca-ATPase PMCA4b, causing increased peak and late sodium current (I Na ) via S-nitrosylation of the cardiac sodium channel. This study determined the prevalence and functional properties of SIDS-associated SNTA1 mutations. Methods and Results-Using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing of SNTA1's open reading frame, 6 rare (absent in 800 reference alleles) missense mutations (G54R, P56S, T262P, S287R, T372M, and G460S) were identified in 8 (Ϸ3%) of 292 SIDS cases. These mutations were engineered using polymerase chain reaction-based overlap extension and were coexpressed heterologously with SCN5A, neuronal nitric oxide synthase, and PMCA4b in HEK293 cells. I Na was recorded using the whole-cell method. A significant 1.4-to 1.5-fold increase in peak I Na and 2.3-to 2.7-fold increase in late I Na compared with controls was evident for S287R-, T372M-, and G460S-SNTA1 and was reversed by a neuronal nitric oxide synthase inhibitor. These 3 mutations also caused a significant depolarizing shift in channel inactivation, thereby increasing the overlap of the activation and inactivation curves to increase window current. Conclusions-Abnormal biophysical phenotypes implicate mutations in SNTA1 as a novel pathogenic mechanism for the subset of channelopathic SIDS. Functional studies are essential to distinguish pathogenic perturbations in channel interacting proteins such as ␣1-syntrophin from similarly rare but innocuous ones. (Circ Arrhythm Electrophysiol. 2009;2:667-676.)

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Section: Discussionmentioning

confidence: 76%

α1-Syntrophin Mutations Identified in Sudden Infant Death Syndrome Cause an Increase in Late Cardiac Sodium Current

Cheng

Norstrand

Medeiros-Domingo

et al. 2009

Circ: Arrhythmia and Electrophysiology

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“…The detailed mechanism for the loss of nNOS suppressing function remains to be determined. Notably, the recently reported influences of common variation involving the nNOS adaptor protein (NOS1AP, a nNOS regulator) on QT interval duration [14-17] and observed association of NOS1AP genetic variants with sudden cardiac death [18] SIDS [19], and drug-associated QT prolongation and arrhythmia [20] have also confirmed the key role of nNOS complex in LQTS-related disorders. Thus, the association of nNOS complex-related proteins with both SCN5A and other cardiac ion channels deserves further study.…”

Section: Discussionmentioning

confidence: 91%

Caveolin-3 suppresses late sodium current by inhibiting nNOS-dependent S-nitrosylation of SCN5A

Cheng

Valdivia

Vaidyanathan

et al. 2013

Journal of Molecular and Cellular Cardiology

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“…Recently, NOS1AP a genetic modifier found to increase the risk of SCD in LQTSC patients 32 was also found to be involved in SIDS 33. However the precise mechanisms by which these SNPs are linked to SIDS are not clear.…”

Section: Discussionmentioning

confidence: 99%

A Common Single Nucleotide Polymorphism Can Exacerbate Long-QT Type 2 Syndrome Leading to Sudden Infant Death

Nof

Cordeiro

Pérez

et al. 2010

Circ Cardiovasc Genet

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Background-Identification of infants at risk for sudden arrhythmic death remains one of the leading challenges of modern medicine. We present a family in which a common polymorphism (single nucleotide polymorphism) inherited from the father, combined with a stop codon mutation inherited from the mother (both asymptomatic), led to 2 cases of sudden infant death. Methods and Results-KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, CACNA1c, CACNB2b, and KCNJ2 genes were amplified and analyzed by direct sequencing. Functional electrophysiological studies were performed with the single nucleotide polymorphism and mutation expressed singly and in combination in Chinese ovary (CHO-K1) and COS-1 cells. An asymptomatic woman presenting after the death of her 2-day-old infant and spontaneous abortion of a second baby in the first trimester was referred for genetic analysis. The newborn infant had nearly incessant ventricular tachycardia while in utero and a prolonged QTc (560 ms). The mother was asymptomatic but displayed a prolonged QTc. Genetic screening of the mother revealed a heterozygous nonsense mutation (P926AfsX14) in KCNH2, predicting a stop codon. The father was asymptomatic with a normal QTc but had a heterozygous polymorphism (K897T) in KCNH2. The baby who died at 2 days of age and the aborted fetus inherited both K897T and P926AfsX14. Heterologous coexpression of K897T and P926AfsX14 led to loss of function of HERG current much greater than expression of K897T or P926AfsX14 alone. Conclusions-Our data suggest that a common polymorphism (K897T) can markedly accentuate the loss of function of mildly defective HERG channels, leading to long-QT syndrome-mediated arrhythmias and sudden infant death.

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SNP association and sequence analysis of the NOS1AP gene in SIDS

Cited by 19 publications

References 9 publications

α1-Syntrophin Mutations Identified in Sudden Infant Death Syndrome Cause an Increase in Late Cardiac Sodium Current

α1-Syntrophin Mutations Identified in Sudden Infant Death Syndrome Cause an Increase in Late Cardiac Sodium Current

Caveolin-3 suppresses late sodium current by inhibiting nNOS-dependent S-nitrosylation of SCN5A

A Common Single Nucleotide Polymorphism Can Exacerbate Long-QT Type 2 Syndrome Leading to Sudden Infant Death

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