Abstract：
WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown.
We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID).
We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.Pro204Arg, p.Leu300Ser, p.Glu607Val) in WNK3 in 14 male individuals from 6 unrelated families. Affected individuals had ID with variable presence of epilepsy and structural brain defects. WNK3 variants cosegregated with the disease in 3 different families with multiple affected individuals. This included 1 large family previously diagnosed with X-linked Prieto syndrome. WNK3 pathogenic missense variants localize to the catalytic domain and impede the inhibitory phosphorylation of the neuronal-specific chloride cotransporter KCC2 at threonine 1007, a site critically regulated during the development of synaptic inhibition.
Pathogenic WNK3 variants cause a rare form of human X-linked ID with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism.
We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID).
We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.Pro204Arg, p.Leu300Ser, p.Glu607Val) in WNK3 in 14 male individuals from 6 unrelated families. Affected individuals had ID with variable presence of epilepsy and structural brain defects. WNK3 variants cosegregated with the disease in 3 different families with multiple affected individuals. This included 1 large family previously diagnosed with X-linked Prieto syndrome. WNK3 pathogenic missense variants localize to the catalytic domain and impede the inhibitory phosphorylation of the neuronal-specific chloride cotransporter KCC2 at threonine 1007, a site critically regulated during the development of synaptic inhibition.
Pathogenic WNK3 variants cause a rare form of human X-linked ID with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism.
摘要：
目的：WNK3激酶（PRKWNK3）通过调节阳离子-氯化物协同转运蛋白参与脑的发育和功能，但是WNK3在人类发育中的作用是未知的。
方法：我们确定了罕见家族性或偶发性智力障碍（ID）个体的外显子组或基因组序列。
结果：我们确定了总共6种不同的母系遗传，半合子，3种功能丧失或3种致病性错义变体（p。Pro204Arg,p.Leu300Ser,p.Glu607Val）在来自6个无关家庭的14个男性个体中的WNK3。受影响的个体患有ID，并伴有癫痫和结构性脑缺陷。WNK3变体在3个不同的家庭中与该疾病分离，有多个受影响的个体。这包括1个以前诊断为X连锁Prieto综合征的大家庭。WNK3致病性错义变体定位于催化结构域，并阻止苏氨酸1007处神经元特异性氯化物协同转运蛋白KCC2的抑制性磷酸化，苏氨酸1007是突触抑制发展过程中受到严格调控的位点。
结论：致病性WNK3变异体可引起一种罕见形式的人类X连锁ID，伴有癫痫和脑结构异常，并暗示KCC2的磷酸化调节受损是一种致病机制。
方法：我们确定了罕见家族性或偶发性智力障碍（ID）个体的外显子组或基因组序列。
结果：我们确定了总共6种不同的母系遗传，半合子，3种功能丧失或3种致病性错义变体（p。Pro204Arg,p.Leu300Ser,p.Glu607Val）在来自6个无关家庭的14个男性个体中的WNK3。受影响的个体患有ID，并伴有癫痫和结构性脑缺陷。WNK3变体在3个不同的家庭中与该疾病分离，有多个受影响的个体。这包括1个以前诊断为X连锁Prieto综合征的大家庭。WNK3致病性错义变体定位于催化结构域，并阻止苏氨酸1007处神经元特异性氯化物协同转运蛋白KCC2的抑制性磷酸化，苏氨酸1007是突触抑制发展过程中受到严格调控的位点。
结论：致病性WNK3变异体可引起一种罕见形式的人类X连锁ID，伴有癫痫和脑结构异常，并暗示KCC2的磷酸化调节受损是一种致病机制。
