Exploring the role of neuromuscular excitability in sudden infant death

探索神经肌肉兴奋性在婴儿猝死中的作用

• 批准号: MR/V037838/1
• 负责人: Emma Matthews
• 金额: $ 33.55万
• 依托单位: St George's, University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV037838%2F1
• 关键词: Exploring; role; neuromuscular; excitability; sudden

Sudden infant death syndrome (SIDS) is the unexpected death of a seemingly healthy infant that remains unexplained despite a thorough investigation of the scene and circumstances of death, a comprehensive post-mortem examination, and a multi-professional review of the available information. It is the leading cause of post-neonatal infant death in high income countries. Five children in the UK die each week from SIDS. Current evidence as to the cause of death proposes convergence of "a triple risk": a vulnerable infant, a critical developmental period and an external stressor e.g. fever. Electrical signals control a muscle's excitability i.e. it's ability to contract and relax. Multiple proteins are responsible for generating and controlling these signals. Mutations in these genes can cause clinical diseases e.g. congenital myasthenia. All of these diseases tend to produce episodic muscle symptoms but in between individuals appear healthy. As they affect a muscle's electrical circuit rather than structure they also leave no post-mortem hallmark. These diseases may impair breathing and be fatal in a manner that is indistinguishable from SIDS. The SCN4A gene codes for one of the most essential proteins for muscle excitability, an ion channel called Nav1.4. Clinical disorders due to mutations in the SCN4A gene cause breathing muscle impairment including life threatening apnoeas (cessation of breathing) in infants. Based on observations I have made in infants I collaborated with my research partner Prof Behr and obtained new genetic and functional evidence that qualitatively similar SCN4A gene variants occur in some cases of (SIDS). I now hypothesise that ion channels like Nav1.4, and other proteins critical for skeletal muscle excitability may collectively account for a larger proportion of SIDS cases (contributing to the vulnerable infant risk) and that normal muscle development may change the clinical severity of these variants in early life. A severity and risk that may get less with age i.e. a critical developmental period. This proposal aims to: 1. Determine the frequency of rare gene variants encoding proteins that influence skeletal muscle excitability in c.700 SIDS cases and UK biobank controls2. Determine the frequency of SIDS amongst families with neuromuscular excitability diseases caused by variants in these same genes3. Characterise the normal developmental changes of muscle fibre types in human skeletal muscle 4. Use a computer model to determine the physiological consequences of combined genetic, developmental and exogenous variables on muscle excitability - the "triple risk"I will use whole exome sequencing data from c.700 DNA samples of infants who have died from SIDS and screen for very rare or new variants in a candidate gene list (genes critical for muscle excitability) that are predicted to affect protein function. The frequency that these gene variants are found in the SIDS cases will be compared with the UK biobank control sequencing data to see if they are more common in SIDS cases. I will also use clinical data from families with mutations in these genes causing clinical disease to ascertain the incidence of sudden infant deaths and whether this is more common than among the general population. Muscles are made up of subtypes of fast and slow fibres. I think the more fast fibres a muscle has the more severe the effect of the gene variants will be and that infants' muscle will have more fast fibres than older children. A fully automated protocol applying different coloured antibodies to the different fibre types in a single skeletal muscle section will be used on human control biopsies from age 0 to 16years to determine the proportion of each fibre type at different ages. A computer model of a muscle fibre will be used to ascertain the individual and combined effects of developmental variables on normal and mutant (with a gene variant) muscle fibre function and performance.

婴儿猝死综合征（SIDS）是一个看似健康的婴儿的意外死亡，尽管对死亡现场和情况进行了彻底的调查，进行了全面的尸检，并对现有信息进行了多专业审查，但仍然无法解释。它是高收入国家新生儿后期死亡的主要原因。英国每周有5名儿童死于SIDS。目前关于死亡原因的证据提出了“三重风险”的汇合：脆弱的婴儿、关键的发育期和外部压力因素，例如发烧。电信号控制肌肉的兴奋性，即收缩和放松的能力。多种蛋白质负责产生和控制这些信号。这些基因的突变可导致临床疾病，例如先天性肌无力。所有这些疾病都倾向于产生偶发性肌肉症状，但在个体之间似乎是健康的。因为它们影响的是肌肉的电路而不是结构，所以它们也不会留下死后的痕迹。这些疾病可能会损害呼吸，并以与SIDS无法区分的方式致命。SCN 4A基因编码肌肉兴奋性最重要的蛋白质之一，即一种称为Nav1.4的离子通道。由于SCN 4A基因突变引起的临床病症导致呼吸肌损伤，包括婴儿中危及生命的呼吸暂停（呼吸停止）。根据我对婴儿的观察，我与我的研究伙伴Behr教授合作，获得了新的遗传和功能证据，证明在某些情况下（SIDS）发生了定性相似的SCN 4A基因变异。我现在假设，离子通道如Nav1.4和其他对骨骼肌兴奋性至关重要的蛋白质可能共同占SIDS病例的更大比例（导致脆弱的婴儿风险），并且正常的肌肉发育可能会改变这些变体在早期生命中的临床严重程度。严重程度和风险可能随着年龄的增长而降低，即关键发育期。 本建议旨在：1.确定罕见的基因变异的频率编码的蛋白质，影响骨骼肌兴奋性的c.700 SIDS的情况下，英国生物库控制2。确定由这些相同基因变异引起的神经肌肉兴奋性疾病家族中SIDS的频率3。描述人体骨骼肌肌纤维类型的正常发育变化4.使用计算机模型来确定组合的遗传，发育和外源性变量对肌肉兴奋性的生理后果-“三重风险”我将使用来自死于SIDS的婴儿的c.700 DNA样本的全外显子组测序数据，并在候选基因列表中筛选非常罕见或新的变异（肌肉兴奋性的关键基因），这些变异预计会影响蛋白质功能。这些基因变异在SIDS病例中发现的频率将与英国生物库对照测序数据进行比较，以确定它们是否在SIDS病例中更常见。我还将使用这些基因突变导致临床疾病的家庭的临床数据，以确定婴儿猝死的发生率，以及这种情况是否比一般人群更常见。肌肉由快纤维和慢纤维的亚型组成。我认为肌肉中的快速纤维越多，基因变异的影响就越严重，婴儿的肌肉将比年龄较大的儿童拥有更多的快速纤维。将对单个骨骼肌切片中的不同纤维类型应用不同颜色抗体的全自动方案用于0至16岁的人类对照活检，以确定不同年龄的每种纤维类型的比例。一个肌肉纤维的计算机模型将用于确定发育变量对正常和突变（具有基因变体）肌肉纤维功能和性能的单独和组合影响。

项目成果

The long exercise test as a functional marker of periodic paralysis.

• DOI: 10.1002/mus.27465
• 发表时间: 2022-05
• 期刊: Muscle & nerve
• 影响因子: 3.4
• 作者: Ribeiro A;Suetterlin KJ;Skorupinska I;Tan SV;Morrow JM;Matthews E;Hanna MG;Fialho D
• 通讯作者: Fialho D

Excitability properties of mouse and human skeletal muscle fibres compared by muscle velocity recovery cycles.

• DOI: 10.1016/j.nmd.2022.02.011
• 发表时间: 2022-04
• 期刊: Neuromuscular disorders : NMD
• 作者: Suetterlin KJ;Männikkö R;Matthews E;Greensmith L;Hanna MG;Bostock H;Tan SV
• 通讯作者: Tan SV

Investigating genotype-phenotype relationship of extreme neuropathic pain disorders in a UK national cohort.

• DOI: 10.1093/braincomms/fcad037
• 发表时间: 2023
• 期刊: Brain communications
• 影响因子: 4.8

Accelerating the genetic diagnosis of neurological disorders presenting with episodic apnoea in infancy

• DOI: 10.1016/s2352-4642(22)00091-8
• 发表时间: 2022-06-15
• 期刊: LANCET CHILD & ADOLESCENT HEALTH
• 影响因子: 36.4
• 作者: Silksmith，Bryony;Munot，Pinki;Matthews，Emma
• 通讯作者: Matthews，Emma

Gene variant effects across sodium channelopathies predict function and guide precision therapy.

• DOI: 10.1093/brain/awac006
• 发表时间: 2022-12-19
• 期刊: Brain : a journal of neurology