Sudden Infant Death Syndrome: Rare Mutation in the Serotonin System FEV Gene

Abstract

Recent studies have identified abnormalities in the development and function of medullary serotonin (5-HT) pathways in postmortem brain from sudden infant death syndrome (SIDS) cases, suggesting 5-HT-mediated dysregulation of the autonomic nervous system (ANS) in SIDS. The human fifth Ewing variant (FEV) gene is specifically expressed in central 5-HT neurons in the brain, with a predicted role in specification and maintenance of serotonergic neuronal phenotype. We hypothesized that variations of FEV may underlie abnormalities of the 5-HT system in SIDS cases and thus may be associated with SIDS risk. To elucidate the relationship between variation in FEV and SIDS, DNA was prepared from 96 African American and Caucasian SIDS cases and 96 genderand ethnicity-matched controls. Standard sequencing and analysis of FEV revealed a heterozygous insertion mutation upstream of the 5= exon 3 splice site occurring more frequently in SIDS cases (6/96) compared with controls (0/96; p ϭ 0.01) and in the overall African American group (6/98) compared with the Caucasian group (0/94; p ϭ 0.03). Identification of a variation in a gene responsible for 5-HT neuronal development, exclusively in a subset of African American SIDS cases in this cohort, may help explain both the observed abnormalities of this system in some SIDS cases and the ethnic disparity observed in SIDS. T he 5-HT system appears to be a key regulator of the ANS with important roles in cardiorespiratory control, thermoregulation, arousal, and sleep-wake cycling (1). Recent studies have identified abnormalities in the development and function of medullary 5-HT pathways in postmortem SIDS brains (2-5). These results indicate possible dysfunction in the differentiation and development of 5-HT neuronal networks in the medulla leading to disruption of the ANS and increased risk of SIDS.Two functional polymorphisms associated with SIDS risk have been identified in the 5-HT transporter gene (SLC6A4, 5-HTT), known to regulate the duration and strength of interactions between 5-HT and its receptors. Narita et al. (6) initially demonstrated an association of a promoter polymorphism of SLC6A4 with risk of SIDS in the Japanese population. These results were subsequently confirmed in African American and Caucasian SIDS cases (7). Further, an intron 2 polymorphism of the SLC6A4 gene has been shown to increase SIDS risk in the African American population (8). Although these results begin to delineate the genetic mechanisms responsible for 5-HT-mediated dysregulation of the ANS in SIDS, the finding of diffuse differentiation and developmental abnormalities of the medullary 5-HT system suggests a genetic mechanism acting in the cascade of genes controlling 5-HT system development.The transcriptional mechanisms leading to differentiation and development of the neuronal 5-HT system have been deciphered in recent studies (9 -14). These studies identified a Sonic hedgehog (Shh)-regulated series of transcription factors working in concert to specify 5-HT neurotransmitter phe...

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“…An increased frequency of a long allele polymorphism, giving an especially high serotonin reuptake, has been found in Japanese SIDS victims 157 , in black 158 , and white American victims (Paterson et al -abstract presented at International congress on sudden unexpected death in Infancy, Soria Moria, Oslo, Nov 2007), and in Norwegian victims (Opdal et al 2008: personal communication). An insertion mutation possibly affecting 5-HT neuronal development was also recently reported in 6 out of 49 black American SIDS victims compared to none of the controls 159 .…”

Genetic Models of Serotonin (5‐HT) Depletion: What do They Tell Us About the Developmental Role of 5‐HT?

“…Altered respiratory control was also noted during early postnatal life, as indicated by irregularities in breathing and increased respiratory pauses (Erickson et al, 2007). Interestingly, genetic variants of FEV in humans have been associated with sudden infant death syndrome, suggesting that there is a link between the development of the serotonin neurons in the brainstem and early postnatal respiratory control (Rand et al, 2007;Broadbelt et al, 2009).…”

Sudden Infant Death Syndrome and Sudden Intrauterine Unexplained Death: Correlation Between Hypoplasia of Raphé Nuclei and Serotonin Transporter Gene Promoter Polymorphism

“…Key positive findings include the promoter region and intron 2 of the serotonin transporter gene (5-HTT) Long (L) allele, the L/L genotype, and the haplotype including the L alleles of both polymorphisms, and low frequency but apparent genetic variants in the FEV gene (11) and the PHOX2B gene (12). These results likely have a role in serotonin network dysfunction, resulting in a failure of autonomic and respiratory responses to hypoxia and/or hypercapnia, potentially resulting in risk for sudden death.…”