Biallelic variants in PSMB1 encoding the proteasome subunit β6 cause impairment of proteasome function, microcephaly, intellectual disability, developmental delay and short stature
Biallelic variants in PSMB1 encoding the proteasome subunit β6 cause impairment of proteasome function, microcephaly, intellectual disability, developmental delay and short stature
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DOI：
10.1093/hmg/ddaa032
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发表时间：
2020-04-01
影响因子：
3.5
通讯作者：
Antonarakis, Stylianos E.
中科院分区：
文献类型：
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作者：
Ansar, Muhammad;Ebstein, Frederic;Antonarakis, Stylianos E.
大多数罕见的常染色体隐性遗传病的分子原因仍然未知。由于广泛的纯合性，血缘关系解开了许多隐性表型，并有利于检测新的基因-疾病的联系。在这里，我们报告了两个兄弟姐妹的表型迹象，包括智力残疾（ID），发育迟缓和小头畸形的巴基斯坦血缘家庭中，我们已经确定了纯合性的p（Tyr 103 His）在PSMB 1基因（Genbank NM_002793）与疾病表型分离。PSMB 1编码β型蛋白酶体亚基（即β 6）。对p（Tyr 103 His）变体的建模表明，该变体削弱了PSMB 1/β 6和PSMA 5/α 5蛋白酶体亚基之间的相互作用，从而使20 S蛋白酶体复合物不稳定。在人SHSYSY细胞中的生化实验显示，p（Tyr 103 His）变体影响PSMB 1/β 6的加工及其掺入蛋白酶体，从而损害蛋白酶体活性。单一psmbl斑马鱼直系同源物的CRISPR/Cas9诱变或吗啉代敲低导致小头畸形、小眼畸形和脑尺寸减小。在人类细胞和斑马鱼中的家族和功能实验中的遗传证据表明，PSMB 1/β 6致病性变体是由于异常蛋白酶体组装导致的ID、小头畸形和发育迟缓的隐性疾病的原因。
The molecular cause of the majority of rare autosomal recessive disorders remains unknown. Consanguinity due to extensive homozygosity unravels many recessive phenotypes and facilitates the detection of novel gene-disease links. Here, we report two siblings with phenotypic signs, including intellectual disability (ID), developmental delay and microcephaly from a Pakistani consanguineous family in which we have identified homozygosity for p(Tyr103His) in the PSMB1 gene (Genbank NM_002793) that segregated with the disease phenotype. PSMB1 encodes a beta-type proteasome subunit (i.e. beta 6). Modeling of the p(Tyr103His) variant indicates that this variant weakens the interactions between PSMB1/beta 6 and PSMA5/alpha 5 proteasome subunits and thus destabilizes the 20S proteasome complex. Biochemical experiments in human SHSYSY cells revealed that the p(Tyr103His) variant affects both the processing of PSMB1/beta 6 and its incorporation into proteasome, thus impairing proteasome activity. CRISPR/Cas9 mutagenesis or morpholino knock-down of the single psmbl zebrafish orthologue resulted in microcephaly, microphthalmia and reduced brain size. Genetic evidence in the family and functional experiments in human cells and zebrafish indicates that PSMB1/beta 6 pathogenic variants are the cause of a recessive disease with ID, microcephaly and developmental delay due to abnormal proteasome assembly.