Mutations in RIPK4 Cause the Autosomal-Recessive Form of Popliteal Pterygium Syndrome
Mutations in RIPK4 Cause the Autosomal-Recessive Form of Popliteal Pterygium Syndrome
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DOI：
10.1016/j.ajhg.2011.11.014
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发表时间：
2012-01-13
影响因子：
9.8
通讯作者：
Akarsu, Nurten A.
中科院分区：
文献类型：
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作者：
Kalay, Ersan;Sezgin, Orhan;Akarsu, Nurten A.
常染色体隐性形式的腘翼状胬肉综合征，也称为Bartsocas-Papas综合征，是一种罕见的，但经常致命的疾病，其特征是与多种先天性畸形相关的明显的腘翼状胬肉。使用Affysse 250 K SNP阵列基因分型和纯合性定位，我们将这种畸形综合征定位到染色体21q22.3区域。RIPK 4（受体相互作用丝氨酸/苏氨酸激酶蛋白4）的直接测序显示纯合颠换（c.362T>A），其导致蛋白质的丝氨酸/苏氨酸激酶结构域中的氨基酸位置121（p.Ile121Asn）处的保守异亮氨酸被天冬酰胺取代。在两个家族中观察到了额外的致病性突变，一个纯合转换（c.551C>T）导致保守位置的错义取代（p.Thr184Ile）和一个纯合的单碱基对插入突变（c.777_778insA），预计会导致激酶结构域中的提前终止密码子（p.Arg260ThrfsX14）。激酶结构域的分子模拟表明，Ile 121和Thr 184位置对于蛋白质的稳定性和激酶活性都是至关重要的。荧光素酶报告基因测定也表明，这些突变对RIPK 4的催化活性至关重要。RIPK 4介导核因子-κ B（NF-κ B）信号通路的活化，并且是角质形成细胞分化以及颅面和肢体发育所必需的。Ripk 4（-/-）小鼠的表型与本文中呈现的人表型一致。此外，在所提出的家族中观察到的畸形谱是相似的，但不如保守的螺旋-环-螺旋遍在激酶（CHUK）缺陷的人胎儿表型严重;称为茧综合征;这种相似性表明RIPK 4和CHUK可能通过密切相关的途径起作用以促进角质形成细胞分化和上皮生长。
The autosomal-recessive form of popliteal pterygium syndrome, also known as Bartsocas-Papas syndrome, is a rare, but frequently lethal disorder characterized by marked popliteal pterygium associated with multiple congenital malformations. Using Affymetrix 250K SNP array genotyping and homozygosity mapping, we mapped this malformation syndrome to chromosomal region 21q22.3. Direct sequencing of RIPK4 (receptor-interacting serine/threonine kinase protein 4) showed a homozygous transversion (c.362T>A) that causes substitution of a conserved isoleucine with asparagine at amino acid position 121 (p.Ile121Asn) in the serine/threonine kinase domain of the protein. Additional pathogenic mutations-a homozygous transition (c.551C>T) that leads to a missense substitution (p.Thr184Ile) at a conserved position and a homozygous one base-pair insertion mutation (c.777_778insA) predicted to lead to a premature stop codon (p.Arg260ThrfsX14) within the kinase domain-were observed in two families. Molecular modeling of the kinase domain showed that both the Ile121 and Thr184 positions are critical for the protein's stability and kinase activity. Luciferase reporter assays also demonstrated that these mutations are critical for the catalytic activity of RIPK4. RIPK4 mediates activation of the nuclear factor-kappa B (NF-kappa B) signaling pathway and is required for keratinocyte differentiation and craniofacial and limb development. The phenotype of Ripk4(-/-) mice is consistent with the human phenotype presented herein. Additionally, the spectrum of malformations observed in the presented families is similar, but less severe than the conserved helix-loop-helix ubiquitous kinase (CHUK)-deficient human fetus phenotype; known as Cocoon syndrome; this similarity indicates that RIPK4 and CHUK might function via closely related pathways to promote keratinocyte differentiation and epithelial growth.