Biallelic variants in PSMB1 encoding the proteasome subunit β6 cause impairment of proteasome function, microcephaly, intellectual disability, developmental delay and short stature

Abstract

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 β-type proteasome subunit (i.e. β6). Modeling of the p(Tyr103His) variant indicates that this variant weakens the interactions between PSMB1/β6 and PSMA5/α5 proteasome subunits and thus destabilizes the 20S proteasome complex. Biochemical experiments in human SHSY5Y cells revealed that the p(Tyr103His) variant affects both the processing of PSMB1/β6 and its incorporation into proteasome, thus impairing proteasome activity. CRISPR/Cas9 mutagenesis or morpholino knock-down of the single psmb1 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/β6 pathogenic variants are the cause of a recessive disease with ID, microcephaly and developmental delay due to abnormal proteasome assembly.

Out of Control: The Role of the Ubiquitin Proteasome System in Skeletal Muscle during Inflammation

“…By now, it is clear that not all discovered proteasome loss-of-function mutations cause severe autoinflammation. Genomic alterations in genes of 19S subunits ( PSMD12 [ 401 ], PSMC3 [ 402 ]) or in PSMB1 encoding β6 [ 403 ] are predominantly characterized by neurodevelopmental disorders and do not present with pronounced autoinflammation [ 47 , 392 ]. In addition to type I IFN, PRAAS patients present with moderate-to-strongly increased serum levels of IL-6 [ 393 , 404 ].…”

Immunoproteasome Function in Normal and Malignant Hematopoiesis

“…Variants in the PSMA6 gene have been linked to coronary artery disease, myocardial infarction, type II diabetes mellitus, and ischemic stroke, while an association between variants in the PSMA7 gene and intellectual disability has been reported [ 112 ]. Recently, two reports have associated variants in the PSMC3 gene with severe congenital deafness, early-onset cataracts, and various neurological features [ 113 ] and PSMΒ1 variants with microcephaly, intellectual disability, developmental delay, and short stature [ 114 ]. Polymorphisms in genes encoding the iP subunits β1i ( PSBM9 ) and β5i ( PSMB8 ) have been associated with an increased risk of tumor development, including the development of esophageal carcinoma [ 115 ], cervical carcinoma [ 116 ], oral squamous cell carcinoma [ 81 , 117 ], prostate cancer [ 118 ], and colon cancer [ 119 ].…”

The Ubiquitin–Proteasome System in Immune Cells

“…Intriguingly, proteasome loss-of-function mutations are not always associated with systemic autoinflammation. Herein, subjects with alterations in PSMD12, PSMC3 or PSMB1 suffer from neurodevelopmental disorders rather than typical CANDLE/PRAAS syndromes [205][206][207][208]. The reason for these varying phenotypes is still unclear and warrants further investigation.…”