Clinical findings of 21 previously unreported probands with <i>HNRNPU</i>‐related syndrome and comprehensive literature review

Durkin, Anna; Albaba, Shadi; Fry, Andrew E.; Morton, Jenny; Douglas, Andrew G.L.; Beleza, Ana; Williams, Denise; Volker‐Touw, Catharina M.L.; Lynch, Sally Ann; Canham, Natalie; Clowes, Virginia; Straub, V.; Lachlan, Katherine; Gibbon, Frances; Gamal, Mayy El; Varghese, Vinod; Parker, Michael; Newbury‐Ecob, Ruth; Turnpenny, Peter D.; Gardham, Alice; Ghali, Neeti; Balasubramanian, Meena

doi:10.1002/ajmg.a.61599

Cited by 25 publications

(35 citation statements)

References 14 publications

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“…Later, a variety of clinical phenotypes related to HNRNPU mutation were reported, mainly including early-onset epilepsy with severe mental retardation, WS, EOEE, Lennox Gastaut syndrome and craniofacial deformity [28][29][30]. Durkin thought that HNRNPU gene mutation related disease is more likely to be a kind of neurodevelopmental syndrome [30]. Durkin reported 21 cases of children, of which 3 cases were onset with febrile convulsion.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic Spectrum and Long-term Outcome in Children With Genetic Causes of Early-onset Epileptic Encephalopathy

Liu

Luo

et al. 2021

Preprint

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Background To explore the clinical phenotype and long-term outcome in children with genetic causes of early-onset epileptic encephalopathies. Methods The clinical data of 118 children between 2010 and 2020 was obtained and analyzed. The whole exome sequencing and copy number variation studies in family were used to find pathogenic mutations. The confirmed mutations were verified by Sanger sequencing. Results Among 118 patients, 39 patients were diagnosed with DS, 18 were WS, 3 were OS, 3 were EME, 2 were MMFSI, 1 was GLUT1 deficiency syndrome, 1 was Pyridoxine dependent epilepsy and 51 were non-symptomatic EOEEs. The initial EEG showed frequent multiple and multifocal sharp waves, spike waves, sharp slow waves or spike slow waves. In the later period, some transformed into infrequent discharging or normal EEG. 112 patients (112/118, 94.9%) showed normal brain MRI, and the remaining 6 had widened extracerebral space. In the later stage, 115 patients were re-examined with brain MRI 1 to 3 times, the widened gap became normal, only 2 had mild brain atrophy. After treatment, 42 patients (42/118, 35.6%) had seizure control. In EOEE-BS, 6 patients were found KCNQ2 mutations and the remaining mutations were SCN2A (n=2), STXBP1 (n=1). After treatment, only 2 patients had seizure control, 6 had uncontrolled seizures and 1 died. 7 patients with dyskinesia were found. 1 patient starting with a febrile convulsion was caused by HNRNPU mutation. SCN1A mutations were detected in 38 patients (38/118, 32.2%), representing the largest proportion. The second common mutations were KCNQ2 mutations in 9 patients. The third one was CDKL5 mutations in 8 patients. Genes associated with ionic channels represented the largest proportion (66/118, 55.9%), sodium channel potassium channel and calcium channel respectively. In WS, we detected SCN3A, SCN2A, SCN8A, CACNA1H, DEPDC5, MECP2, DYNC1H1, CDKL5, ALG11, CCDC88C, GABAA1, IL1RAPL1, RNASEH2B, SLC19A3, STXBP1, QARS, COL4A2 mutations. In addition to common gene mutations, we reported rare possible pathogenic genes: CCDC88C, IL1RAPL1, RNASEH2B and COL4A2 in WS. In non-syndromic genetic causes of EOEEs, we detected rare possible pathogenic genes: SETBP1, DPYD, CSNK2B and H3F3A. As for genetic modes, denovo heterozygous mutations account for the largest proportion (104/118, 88.1%). 3 patients with SMC1A mutations response to KD add-on therapy. VPA added treatment showed good effects on KCNB1 and PACS2 encephalopathy. LEV showed good effects on STXBP1, and OXC showed good effects on SCN8A encephalopathy. Conclusion The clinical manifestations of EOEE are variable, including dyskinesia. EOEE-BS usually response poorly to AEDS therapy. Although some patients achieve seizure-free, there is no remarkable improvement in their development. EOEEs starting with a febrile convulsion may be a special phenotype of HNRNPU related neurodevelopmental syndrome, similar to DS. We report rare possible pathogenic genes: CCDC88C, IL1RAPL1, RNASEH2B, COL4A2 in WS and detect rare possible pathogenic genes: SETBP1, DPYD, CSNK2B and H3F3A in non-syndromic genetic causes of EOEEs. Although genetic causes of EOEEs response poorly to AEDS treatment, we find that some gene mutation related EOEEs receive good effects on specific AEDS.

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Section: Discussionmentioning

confidence: 99%

Phenotypic Spectrum and Long-term Outcome in Children With Genetic Causes of Early-onset Epileptic Encephalopathy

Liu

Luo

et al. 2021

Preprint

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“…Replication stress is an important hallmark of cancer (Gaillard et al, 2015; Macheret and Halazonetis, 2015), and an intriguing possibility is that SAF-A is important for cancer cell survival in the context of such replication stress. Conversely, SAF-A loss-of-function alleles are linked to developmental disorders including microcephaly (Durkin et al, 2020; Leduc et al, 2017; Yates et al, 2017). Overall, our findings reported here show that the promotion of robust DNA replication by SAF-A is crucial for its role in supporting cellular capacity for proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…This increased expression suggests that SAF-A contributes to the formation or survival of cancer cells in a dose-dependent manner. Conversely, SAF-A loss-of-function alleles are linked to developmental disorders including microcephaly (Durkin et al, 2020; Leduc et al, 2017; Yates et al, 2017). Overall, these observations suggest a positive role for SAF-A in promoting cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

SAF-A promotes origin licensing and replication fork progression to ensure robust DNA replication

Connolly

Takahashi

Miura

et al. 2021

Preprint

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The organisation of chromatin is closely intertwined with biological activities of chromosome domains, including transcription and DNA replication status. Scaffold attachment factor A (SAF-A), also known as Heteronuclear Ribonucleoprotein Protein U (HNRNPU), contributes to the formation of open chromatin structure. Here we demonstrate that SAF-A promotes the normal progression of DNA replication, and enables resumption of replication after inhibition. We report that cells depleted for SAF-A show reduced origin licensing in G1 phase, and consequently reduced origin activation frequency in S phase. Replication forks progress slowly in cells depleted for SAF-A, also contributing to reduced DNA synthesis rate. Single-cell replication timing analysis revealed that the boundaries between early- and late- replicating domains are blurred in cells depleted for SAF-A. Associated with these defects, SAF-A-depleted cells show elevated gH2A phosphorylation and tend to enter quiescence. Overall we find that SAF-A protein promotes robust DNA replication to ensure continuing cell proliferation.

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“…A rare cohort of patients have been identified in which heterozygous mutations in HNRNPU are associated with intellectual disability and muscle weakness [ 291 , 292 , 293 , 294 ]. hnRNP-U is a multifunctional RBP, directly involved in regulating alternative splicing [ 295 , 296 , 297 ], genome architecture [ 298 ], X-chromosome inactivation [ 299 ], and is known to promote the DNA base repair through its interaction with NEIL1 [ 300 ].…”

Section: Unexpected Linksmentioning

confidence: 99%

Influence of Age on Skeletal Muscle Hypertrophy and Atrophy Signaling: Established Paradigms and Unexpected Links

Lee

Neppl

2021

Genes

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Skeletal muscle atrophy in an inevitable occurrence with advancing age, and a consequence of disease including cancer. Muscle atrophy in the elderly is managed by a regimen of resistance exercise and increased protein intake. Understanding the signaling that regulates muscle mass may identify potential therapeutic targets for the prevention and reversal of muscle atrophy in metabolic and neuromuscular diseases. This review covers the major anabolic and catabolic pathways that regulate skeletal muscle mass, with a focus on recent progress and potential new players.

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Clinical findings of 21 previously unreported probands with HNRNPU‐related syndrome and comprehensive literature review

Cited by 25 publications

References 14 publications

Phenotypic Spectrum and Long-term Outcome in Children With Genetic Causes of Early-onset Epileptic Encephalopathy

Phenotypic Spectrum and Long-term Outcome in Children With Genetic Causes of Early-onset Epileptic Encephalopathy

SAF-A promotes origin licensing and replication fork progression to ensure robust DNA replication

Influence of Age on Skeletal Muscle Hypertrophy and Atrophy Signaling: Established Paradigms and Unexpected Links

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