Abstract：
OBJECTIVE: Epigenetic dysregulation has been associated with many inherited disorders. RBBP5 (HGNC:9888) encodes a core member of the protein complex that methylates histone 3 lysine-4 (H3K4) and has not been implicated in human disease.
METHODS: We identify five unrelated individuals with de novo heterozygous variants in RBBP5. Three nonsense/frameshift and two missense variants were identified in probands with neurodevelopmental symptoms including global developmental delay, intellectual disability, microcephaly, and short stature. Here, we investigate the pathogenicity of the variants through protein structural analysis and transgenic Drosophila models.
RESULTS: Both missense p.(T232I) and p.(E296D) variants affect evolutionarily conserved amino acids located at the interface between RBBP5 and the nucleosome. In Drosophila, overexpression analysis identifies partial loss-of-function mechanisms when the variants are expressed using the fly Rbbp5 or human RBBP5 cDNA. Loss of Rbbp5 leads to a reduction in brain size. The human reference or variant transgenes fail to rescue this loss and expression of either missense variant in an Rbbp5 null background results in a less severe microcephaly phenotype than the human reference, indicating both missense variants are partial loss-of-function alleles.
CONCLUSIONS: Haploinsufficiency of RBBP5 observed through de novo null and hypomorphic loss-of-function variants is associated with a syndromic neurodevelopmental disorder.
METHODS: We identify five unrelated individuals with de novo heterozygous variants in RBBP5. Three nonsense/frameshift and two missense variants were identified in probands with neurodevelopmental symptoms including global developmental delay, intellectual disability, microcephaly, and short stature. Here, we investigate the pathogenicity of the variants through protein structural analysis and transgenic Drosophila models.
RESULTS: Both missense p.(T232I) and p.(E296D) variants affect evolutionarily conserved amino acids located at the interface between RBBP5 and the nucleosome. In Drosophila, overexpression analysis identifies partial loss-of-function mechanisms when the variants are expressed using the fly Rbbp5 or human RBBP5 cDNA. Loss of Rbbp5 leads to a reduction in brain size. The human reference or variant transgenes fail to rescue this loss and expression of either missense variant in an Rbbp5 null background results in a less severe microcephaly phenotype than the human reference, indicating both missense variants are partial loss-of-function alleles.
CONCLUSIONS: Haploinsufficiency of RBBP5 observed through de novo null and hypomorphic loss-of-function variants is associated with a syndromic neurodevelopmental disorder.
摘要：
目的：表观遗传失调与许多遗传性疾病有关。RBBP5(HGNC:9888)编码使组蛋白3赖氨酸-4(H3K4)甲基化的蛋白质复合物的核心成员,并且与人类疾病无关。
方法：我们在RBBP5中鉴定了五个具有从头杂合变异的无关个体。在具有神经发育症状的先证者中发现了三个无意义/移码和两个错义变体，包括整体发育迟缓，智力残疾,小头畸形,身材矮小。这里,我们通过蛋白质结构分析和转基因果蝇模型研究变异体的致病性。
结果：错义p。（T232I）和p。（E296D）变体都影响位于RBBP5和核小体之间界面的进化上保守的氨基酸。在果蝇中,过表达分析鉴定了当使用flyRbbp5或人RBBP5cDNA表达变体时的部分功能丧失机制。Rbbp5的丢失导致脑尺寸的减小。人类参考或变体转基因未能挽救这种损失，并且在Rbbp5无效背景中表达任何一种错义变体导致的小头畸形表型比人类参考的严重程度低。表明两种错义变体都是部分功能丧失等位基因。
结论：通过从头缺失和低形功能丧失变异观察到的RBBP5单倍功能不全与综合征性神经发育障碍相关。
方法：我们在RBBP5中鉴定了五个具有从头杂合变异的无关个体。在具有神经发育症状的先证者中发现了三个无意义/移码和两个错义变体，包括整体发育迟缓，智力残疾,小头畸形,身材矮小。这里,我们通过蛋白质结构分析和转基因果蝇模型研究变异体的致病性。
结果：错义p。（T232I）和p。（E296D）变体都影响位于RBBP5和核小体之间界面的进化上保守的氨基酸。在果蝇中,过表达分析鉴定了当使用flyRbbp5或人RBBP5cDNA表达变体时的部分功能丧失机制。Rbbp5的丢失导致脑尺寸的减小。人类参考或变体转基因未能挽救这种损失，并且在Rbbp5无效背景中表达任何一种错义变体导致的小头畸形表型比人类参考的严重程度低。表明两种错义变体都是部分功能丧失等位基因。
结论：通过从头缺失和低形功能丧失变异观察到的RBBP5单倍功能不全与综合征性神经发育障碍相关。
