Biallelic variants in PSMB1 encoding the proteasome subunit β6 cause impairment of proteasome function, microcephaly, intellectual disability, developmental delay and short stature
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 intellect...
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| Published in | Human molecular genetics Vol. 29; no. 7; pp. 1132 - 1143 |
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| Main Authors | , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
England
08.05.2020
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| Online Access | Get full text |
| ISSN | 0964-6906 1460-2083 1460-2083 |
| DOI | 10.1093/hmg/ddaa032 |
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| 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. |
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| AbstractList | 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.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. 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. |
| Author | Özkoç, Hayriye Ebstein, Frédéric Ahmed, Jawad Ansar, Muhammad Bachmann-Gagescu, Ruxandra Santoni, Federico A Zoete, Vincent Iwaszkiewicz, Justyna Sarwar, Muhammad T Ranza, Emmanuelle Paracha, Sohail A Gesemann, Matthias Antonarakis, Stylianos E Krüger, Elke |
| Author_xml | – sequence: 1 givenname: Muhammad surname: Ansar fullname: Ansar, Muhammad organization: Department of Genetic Medicine and Development, University of Geneva, Geneva 1211, Switzerland – sequence: 2 givenname: Frédéric surname: Ebstein fullname: Ebstein, Frédéric organization: Institut für Medizinische Biochemie und Molekularbiologie, Universitätsmedizin Greifswald, Greifswald 17475, Germany – sequence: 3 givenname: Hayriye surname: Özkoç fullname: Özkoç, Hayriye organization: Institute of Medical Genetics, University of Zurich, Schlieren 8952, Switzerland – sequence: 4 givenname: Sohail A surname: Paracha fullname: Paracha, Sohail A organization: Institute of Basic Medical Sciences, Khyber Medical University, Peshawar 25100, Pakistan – sequence: 5 givenname: Justyna surname: Iwaszkiewicz fullname: Iwaszkiewicz, Justyna organization: Molecular Modeling Group, Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland – sequence: 6 givenname: Matthias surname: Gesemann fullname: Gesemann, Matthias organization: Department of Molecular Life Sciences, University of Zurich, Zurich 8057, Switzerland – sequence: 7 givenname: Vincent surname: Zoete fullname: Zoete, Vincent organization: Molecular Modeling Group, Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland, Department of Fundamental Oncology, Ludwig Institute for Cancer Research, Lausanne University, Epalinges 1066, Switzerland – sequence: 8 givenname: Emmanuelle surname: Ranza fullname: Ranza, Emmanuelle organization: Department of Genetic Medicine and Development, University of Geneva, Geneva 1211, Switzerland, Service of Genetic Medicine, University Hospitals of Geneva, Geneva 1205, Switzerland – sequence: 9 givenname: Federico A surname: Santoni fullname: Santoni, Federico A organization: Department of Genetic Medicine and Development, University of Geneva, Geneva 1211, Switzerland, Department of Endocrinology Diabetes and Metabolism, Lausanne University Hospital, Lausanne 1011, Switzerland – sequence: 10 givenname: Muhammad T surname: Sarwar fullname: Sarwar, Muhammad T organization: Institute of Basic Medical Sciences, Khyber Medical University, Peshawar 25100, Pakistan – sequence: 11 givenname: Jawad surname: Ahmed fullname: Ahmed, Jawad organization: Institute of Basic Medical Sciences, Khyber Medical University, Peshawar 25100, Pakistan – sequence: 12 givenname: Elke surname: Krüger fullname: Krüger, Elke organization: Institut für Medizinische Biochemie und Molekularbiologie, Universitätsmedizin Greifswald, Greifswald 17475, Germany – sequence: 13 givenname: Ruxandra surname: Bachmann-Gagescu fullname: Bachmann-Gagescu, Ruxandra organization: Institute of Medical Genetics, University of Zurich, Schlieren 8952, Switzerland, Department of Molecular Life Sciences, University of Zurich, Zurich 8057, Switzerland – sequence: 14 givenname: Stylianos E surname: Antonarakis fullname: Antonarakis, Stylianos E organization: Department of Genetic Medicine and Development, University of Geneva, Geneva 1211, Switzerland, Service of Genetic Medicine, University Hospitals of Geneva, Geneva 1205, Switzerland, iGE3 Institute of Genetics and Genomics of Geneva, Geneva 1211, Switzerland |
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