Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment

Fiordaliso, Sarah K.; Iwata‐Otsubo, Aiko; Ritter, Alyssa; Quesnel-Vallières, Mathieu; Fujiki, Katsunori; Nishi, Eriko; Hančárová, Miroslava; Miyake, Noriko; Morton, Jenny; Lee, Sang Moon; Hackmann, Karl; Bando, Masashige; Masuda, Koji; Nakato, Ryuichiro; Arakawa, Michiko; Bhoj, Elizabeth; Li, Dong; Hákonarson, Hákon; Takeda, Ryojun; Harr, Margaret; Keena, Beth; Zackai, Elaine H.; Okamoto, Nobuhiko; Mizuno, Seiji; Ko, Jung Min; Valachová, Alica; Prchalová, Darina; Vlčková, Markéta; Pippucci, Tommaso; Seiler, Christoph; Choi, Murim; Matsumoto, Naomichi; Donato, Nataliya Di; Barash, Yoseph; Sedláček, Zdeněk; Shirahige, Katsuhiko; Izumi, Kosuke

doi:10.1016/j.ajhg.2019.09.009

Cited by 14 publications

(28 citation statements)

References 21 publications

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“…Mutations in several C* proteins, such as NKAP, FAM50A, and CXORF56, whose genes are located on the X chromosome, are linked to intellectual disabilities (34)(35)(36). Guided by CXMS and Al-phaFold structural predictions, we could map regions of the newly identified C* proteins FAM50A and CXORF56, as well as TLS1, close to the CACTIN BSD .…”

Section: Indirect Modulation Of 3′ss Selection By Tls1 Cxorf56 and Fa...mentioning

confidence: 99%

Regulation of 3′ splice site selection after step 1 of splicing by spliceosomal C* proteins

Dybkov¹,

Preußner

Ayoubi³

et al. 2023

Sci. Adv.

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Alternative precursor messenger RNA splicing is instrumental in expanding the proteome of higher eukaryotes, and changes in 3′ splice site (3'ss) usage contribute to human disease. We demonstrate by small interfering RNA–mediated knockdowns, followed by RNA sequencing, that many proteins first recruited to human C* spliceosomes, which catalyze step 2 of splicing, regulate alternative splicing, including the selection of alternatively spliced NAGNAG 3′ss. Cryo–electron microscopy and protein cross-linking reveal the molecular architecture of these proteins in C* spliceosomes, providing mechanistic and structural insights into how they influence 3'ss usage. They further elucidate the path of the 3′ region of the intron, allowing a structure-based model for how the C* spliceosome potentially scans for the proximal 3′ss. By combining biochemical and structural approaches with genome-wide functional analyses, our studies reveal widespread regulation of alternative 3′ss usage after step 1 of splicing and the likely mechanisms whereby C* proteins influence NAGNAG 3′ss choices.

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Section: Indirect Modulation Of 3′ss Selection By Tls1 Cxorf56 and Fa...mentioning

confidence: 99%

Regulation of 3′ splice site selection after step 1 of splicing by spliceosomal C* proteins

Dybkov¹,

Preußner

Ayoubi³

et al. 2023

Sci. Adv.

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“…NKAP is a conserved protein comprised of 415 amino acids, and is assumed to play an important role in hematopoiesis. Males with NKAP germline missense mutations exhibit developmental delay, hypotonia, joint contractures, behavioral abnormalities, Marfanoid habitus, and scoliosis [37]. NKAP deficiency reduces hematopoiesis of stem cells and increases their apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms of Skewed X-Chromosome Inactivation in Female Hemophilia Patients—Lessons from Wide Genome Analyses

Dardik

Avishai

Lalezari

et al. 2021

IJMS

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Introduction: Hemophilia A (HA) is an X-linked bleeding disorder caused by factor VIII (FVIII) deficiency or dysfunction due to F8 gene mutations. HA carriers are usually asymptomatic because their FVIII levels correspond to approximately half of the concentration found in healthy individuals. However, in rare cases, a carrier may exhibit symptoms of moderate to severe HA primarily due to skewed inactivation of her non-hemophilic X chromosome. Aim: The aim of the study was to investigate X-chromosome inactivation (XCI) patterns in HA carriers, with special emphasis on three karyotypically normal HA carriers presenting with moderate to severe HA phenotype due to skewed XCI, in an attempt to elucidate the molecular mechanism underlying skewed XCI in these symptomatic HA carriers. The study was based on the hypothesis that the presence of a pathogenic mutation on the non-hemophilic X chromosome is the cause of extreme inactivation of that X chromosome. Methods: XCI patterns were studied by PCR analysis of the CAG repeat region in the HUMARA gene. HA carriers that demonstrated skewed XCI were further studied by whole-exome sequencing (WES) followed by X chromosome-targeted bioinformatic analysis. Results: All three HA carriers presenting with the moderate to severe HA phenotype due to skewed XCI were found to carry pathogenic mutations on their non-hemophilic X chromosomes. Patient 1 was diagnosed with a frameshift mutation in the PGK1 gene that was associated with familial XCI skewing in three generations. Patient 2 was diagnosed with a missense mutation in the SYTL4 gene that was associated with familial XCI skewing in two generations. Patient 3 was diagnosed with a nonsense mutation in the NKAP gene that was associated with familial XCI skewing in two generations. Conclusion: Our results indicate that the main reason for skewed XCI in our female HA patients was negative selection against cells with a disadvantage caused by an additional deleterious mutation on the silenced X chromosome, thus complicating the phenotype of a monogenic X-linked disease. Based on our study, we are currently offering the X inactivation test to symptomatic hemophilia carriers and plan to expand this approach to symptomatic carriers of other X-linked diseases, which can be further used in pregnancy planning.

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“…IF was performed as previously described [42]. HEK293T cells were settled on poly-lysine coated coverslips and transfected with the CBX1 cDNA vector.…”

Section: Methodsmentioning

confidence: 99%

Dominant-negative mutations inCBX1cause a neurodevelopmental disorder

Iwata‐Otsubo

Lindsay-Temple

Dias

et al. 2020

Preprint

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The heterochromatin protein 1 (HP1) family of proteins represents an essential structural component of heterochromatin formation and organization. There are three HP1 proteins (HP1α, HP1β, and HP1γ), and HP1β is the only essential HP1 protein during mammalian development. Here we report a neurodevelopmental disorder due to missense mutations in the CBX1 gene which encodes HP1β. Two unrelated individuals were found to have de novo missense mutations in CBX1. Their clinical features include developmental delay, hypotonia and autistic features, suggesting the importance of HP1β in neuronal function. Identified mutations are in a known functional domain, chromodomain, and the identified mutations abolished HP1β-chromatin interactions. Our transcriptome and epigenome analyses revealed that reduced HP1β chromatin affects gene expression of H3K27me3 marked genes, suggesting the importance of HP1β in facultative hetrochromatin organization during human development. This diagnosis represents the first genetic disorder due to germline mutations in genes encoding HP1 proteins.

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Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment

Cited by 14 publications

References 21 publications

Regulation of 3′ splice site selection after step 1 of splicing by spliceosomal C* proteins

Regulation of 3′ splice site selection after step 1 of splicing by spliceosomal C* proteins

Molecular Mechanisms of Skewed X-Chromosome Inactivation in Female Hemophilia Patients—Lessons from Wide Genome Analyses

Dominant-negative mutations inCBX1cause a neurodevelopmental disorder

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