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Article ; Online: The Emerging Roles of Long Non-Coding RNAs in Intellectual Disability and Related Neurodevelopmental Disorders

Carla Liaci / Lucia Prandi / Lisa Pavinato / Alfredo Brusco / Mara Maldotti / Ivan Molineris / Salvatore Oliviero / Giorgio R. Merlo

International Journal of Molecular Sciences, Vol 23, Iss 6118, p

2022 Volume 6118

Abstract: In the human brain, long non-coding RNAs (lncRNAs) are widely expressed in an exquisitely temporally and spatially regulated manner, thus suggesting their contribution to normal brain development and their probable involvement in the molecular pathology ... ...

Abstract	In the human brain, long non-coding RNAs (lncRNAs) are widely expressed in an exquisitely temporally and spatially regulated manner, thus suggesting their contribution to normal brain development and their probable involvement in the molecular pathology of neurodevelopmental disorders (NDD). Bypassing the classic protein-centric conception of disease mechanisms, some studies have been conducted to identify and characterize the putative roles of non-coding sequences in the genetic pathogenesis and diagnosis of complex diseases. However, their involvement in NDD, and more specifically in intellectual disability (ID), is still poorly documented and only a few genomic alterations affecting the lncRNAs function and/or expression have been causally linked to the disease endophenotype. Considering that a significant fraction of patients still lacks a genetic or molecular explanation, we expect that a deeper investigation of the non-coding genome will unravel novel pathogenic mechanisms, opening new translational opportunities. Here, we present evidence of the possible involvement of many lncRNAs in the etiology of different forms of ID and NDD, grouping the candidate disease-genes in the most frequently affected cellular processes in which ID-risk genes were previously collected. We also illustrate new approaches for the identification and prioritization of NDD-risk lncRNAs, together with the current strategies to exploit them in diagnosis.
Keywords	lncRNAs ; intellectual disability ; neurodevelopmental disorders ; gene networks ; neuronal differentiation ; systems biology ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: KCNK18 Biallelic Variants Associated with Intellectual Disability and Neurodevelopmental Disorders Alter TRESK Channel Activity

Lisa Pavinato / Ehsan Nematian-Ardestani / Andrea Zonta / Silvia De Rubeis / Joseph Buxbaum / Cecilia Mancini / Alessandro Bruselles / Marco Tartaglia / Mauro Pessia / Stephen J. Tucker / Maria Cristina D’Adamo / Alfredo Brusco

International Journal of Molecular Sciences, Vol 22, Iss 6064, p

2021 Volume 6064

Abstract: The TWIK-related spinal cord potassium channel (TRESK) is encoded by KCNK18 , and variants in this gene have previously been associated with susceptibility to familial migraine with aura (MIM #613656). A single amino acid substitution in the same protein, ...

Abstract	The TWIK-related spinal cord potassium channel (TRESK) is encoded by KCNK18 , and variants in this gene have previously been associated with susceptibility to familial migraine with aura (MIM #613656). A single amino acid substitution in the same protein, p.Trp101Arg, has also been associated with intellectual disability (ID), opening the possibility that variants in this gene might be involved in different disorders. Here, we report the identification of KCNK18 biallelic missense variants (p.Tyr163Asp and p.Ser252Leu) in a family characterized by three siblings affected by mild-to-moderate ID, autism spectrum disorder (ASD) and other neurodevelopment-related features. Functional characterization of the variants alone or in combination showed impaired channel activity. Interestingly, Ser252 is an important regulatory site of TRESK, suggesting that alteration of this residue could lead to additive downstream effects. The functional relevance of these mutations and the observed co-segregation in all the affected members of the family expand the clinical variability associated with altered TRESK function and provide further insight into the relationship between altered function of this ion channel and human disease.
Keywords	KCNK18 ; TRESK ; K2P ; intellectual disability ; potassium channel ; autism spectrum disorder ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	572
Language	English
Publishing date	2021-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A Novel CCT5 Missense Variant Associated with Early Onset Motor Neuropathy

Vincenzo Antona / Federica Scalia / Elisa Giorgio / Francesca C. Radio / Alfredo Brusco / Massimiliano Oliveri / Giovanni Corsello / Fabrizio Lo Celso / Maria Vadalà / Everly Conway de Macario / Alberto J. L. Macario / Francesco Cappello / Mario Giuffrè

International Journal of Molecular Sciences, Vol 21, Iss 7631, p

2020 Volume 7631

Abstract: Diseases associated with acquired or genetic defects in members of the chaperoning system (CS) are increasingly found and have been collectively termed chaperonopathies. Illustrative instances of genetic chaperonopathies involve the genes for chaperonins ...

Abstract	Diseases associated with acquired or genetic defects in members of the chaperoning system (CS) are increasingly found and have been collectively termed chaperonopathies. Illustrative instances of genetic chaperonopathies involve the genes for chaperonins of Groups I (e.g., Heat shock protein 60, Hsp60 ) and II (e.g., Chaperonin Containing T-Complex polypeptide 1, CCT ). Examples of the former are hypomyelinating leukodystrophy 4 (HLD4 or MitCHAP60) and hereditary spastic paraplegia (SPG13). A distal sensory mutilating neuropathy has been linked to a mutation [p.(His147Arg)] in subunit 5 of the CCT5 gene. Here, we describe a new possibly pathogenic variant [p.(Leu224Val)] of the same subunit but with a different phenotype. This yet undescribed disease affects a girl with early onset demyelinating neuropathy and a severe motor disability. By whole exome sequencing (WES), we identified a homozygous CCT5 c.670C>G p.(Leu224Val) variant in the CCT5 gene. In silico 3D-structure analysis and bioinformatics indicated that this variant could undergo abnormal conformation and could be pathogenic. We compared the patient’s clinical, neurophysiological and laboratory data with those from patients carrying p.(His147Arg) in the equatorial domain. Our patient presented signs and symptoms absent in the p.(His147Arg) cases. Molecular dynamics simulation and modelling showed that the Leu224Val mutation that occurs in the CCT5 intermediate domain near the apical domain induces a conformational change in the latter. Noteworthy is the striking difference between the phenotypes putatively linked to mutations in the same CCT subunit but located in different structural domains, offering a unique opportunity for elucidating their distinctive roles in health and disease
Keywords	CCT5 ; chaperonins ; chaperoning system ; genetic variants ; mutation ; genetic chaperonopathies ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	572
Language	English
Publishing date	2020-10-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Enhancer hijacking at the ARHGAP36 locus is associated with connective tissue to bone transformation

Uirá Souto Melo / Jerome Jatzlau / Cesar A. Prada-Medina / Elisabetta Flex / Sunhild Hartmann / Salaheddine Ali / Robert Schöpflin / Laura Bernardini / Andrea Ciolfi / M-Hossein Moeinzadeh / Marius-Konstantin Klever / Aybuge Altay / Pedro Vallecillo-García / Giovanna Carpentieri / Massimo Delledonne / Melanie-Jasmin Ort / Marko Schwestka / Giovanni Battista Ferrero / Marco Tartaglia /

Alfredo Brusco / Manfred Gossen / Dirk Strunk / Sven Geißler / Stefan Mundlos / Sigmar Stricker / Petra Knaus / Elisa Giorgio / Malte Spielmann

Nature Communications, Vol 14, Iss 1, Pp 1-

2023 Volume 13

Abstract: Abstract Heterotopic ossification is a disorder caused by abnormal mineralization of soft tissues in which signaling pathways such as BMP, TGFβ and WNT are known key players in driving ectopic bone formation. Identifying novel genes and pathways related ... ...

Abstract	Abstract Heterotopic ossification is a disorder caused by abnormal mineralization of soft tissues in which signaling pathways such as BMP, TGFβ and WNT are known key players in driving ectopic bone formation. Identifying novel genes and pathways related to the mineralization process are important steps for future gene therapy in bone disorders. In this study, we detect an inter-chromosomal insertional duplication in a female proband disrupting a topologically associating domain and causing an ultra-rare progressive form of heterotopic ossification. This structural variant lead to enhancer hijacking and misexpression of ARHGAP36 in fibroblasts, validated here by orthogonal in vitro studies. In addition, ARHGAP36 overexpression inhibits TGFβ, and activates hedgehog signaling and genes/proteins related to extracellular matrix production. Our work on the genetic cause of this heterotopic ossification case has revealed that ARHGAP36 plays a role in bone formation and metabolism, outlining first details of this gene contributing to bone-formation and -disease.
Keywords	Science ; Q
Subject code	570
Language	English
Publishing date	2023-04-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Congenital Sensorineural Hearing Loss and Inborn Pigmentary Disorders

Laura Cristina Gironi / Enrico Colombo / Alfredo Brusco / Enrico Grosso / Valeria Giorgia Naretto / Andrea Guala / Eleonora Di Gregorio / Andrea Zonta / Francesca Zottarelli / Barbara Pasini / Paola Savoia

Medicina, Vol 55, Iss 7, p

First Report of Multilocus Syndrome in Piebaldism

2019 Volume 345

Abstract: Congenital sensorineural hearing loss may occur in association with inborn pigmentary defects of the iris, hair, and skin. These conditions, named auditory-pigmentary disorders (APDs), represent extremely heterogeneous hereditary diseases, including ... ...

Abstract	Congenital sensorineural hearing loss may occur in association with inborn pigmentary defects of the iris, hair, and skin. These conditions, named auditory-pigmentary disorders (APDs), represent extremely heterogeneous hereditary diseases, including Waardenburg syndromes, oculocutaneous albinism, Tietz syndrome, and piebaldism. APDs are part of the neurocristopathies, a group of congenital multisystem disorders caused by an altered development of the neural crest cells, multipotent progenitors of a wide variety of different lineages, including those differentiating into peripheral nervous system glial cells and melanocytes. We report on clinical and genetic findings of two monozygotic twins from a large Albanian family who showed a complex phenotype featured by sensorineural congenital deafness, severe neuropsychiatric impairment, and inborn pigmentary defects of hair and skin. The genetic analyzes identified, in both probands, an unreported co-occurrence of a new heterozygous germline pathogenic variant (c.2484 + 5G > T splicing mutation) in the KIT gene, consistent with the diagnosis of piebaldism, and a heterozygous deletion at chromosome 15q13.3, responsible for the neuropsychiatric impairment. This case represents the first worldwide report of dual locus inherited syndrome in piebald patients affected by a complex auditory-pigmentary multisystem phenotype. Here we also synthesize the clinical and genetic findings of all known neurocristopathies characterized by a hypopigmentary congenital disorder.
Keywords	genodermatoses ; genetic skin disorders ; auditory-pigmentary disorders ; neurocristopathies ; piebaldism ; multilocus syndrome ; KIT ; 15q13.3 deletion ; Medicine (General) ; R5-920
Subject code	610
Language	English
Publishing date	2019-07-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: CCG•CGG interruptions in high‐penetrance SCA8 families increase RAN translation and protein toxicity

Barbara A Perez / Hannah K Shorrock / Monica Banez‐Coronel / Tao Zu / Lisa EL Romano / Lauren A Laboissonniere / Tammy Reid / Yoshio Ikeda / Kaalak Reddy / Christopher M Gomez / Thomas Bird / Tetsuo Ashizawa / Lawrence J Schut / Alfredo Brusco / J Andrew Berglund / Lis F Hasholt / Jorgen E Nielsen / SH Subramony / Laura PW Ranum

EMBO Molecular Medicine, Vol 13, Iss 11, Pp n/a-n/a (2021)

2021

Abstract: Abstract Spinocerebellar ataxia type 8 (SCA8), a dominantly inherited neurodegenerative disorder caused by a CTG•CAG expansion, is unusual because most individuals that carry the mutation do not develop ataxia. To understand the variable penetrance of ... ...

Abstract	Abstract Spinocerebellar ataxia type 8 (SCA8), a dominantly inherited neurodegenerative disorder caused by a CTG•CAG expansion, is unusual because most individuals that carry the mutation do not develop ataxia. To understand the variable penetrance of SCA8, we studied the molecular differences between highly penetrant families and more common sporadic cases (82%) using a large cohort of SCA8 families (n = 77). We show that repeat expansion mutations from individuals with multiple affected family members have CCG•CGG interruptions at a higher frequency than sporadic SCA8 cases and that the number of CCG•CGG interruptions correlates with age at onset. At the molecular level, CCG•CGG interruptions increase RNA hairpin stability, and in cell culture experiments, increase p‐eIF2α and polyAla and polySer RAN protein levels. Additionally, CCG•CGG interruptions, which encode arginine interruptions in the polyGln frame, increase toxicity of the resulting proteins. In summary, SCA8 CCG•CGG interruptions increase polyAla and polySer RAN protein levels, polyGln protein toxicity, and disease penetrance and provide novel insight into the molecular differences between SCA8 families with high vs. low disease penetrance.
Keywords	cis‐modifier ; RAN translation ; reduced penetrance ; sequence interruptions ; spinocerebellar ataxia type 8 ; Medicine (General) ; R5-920 ; Genetics ; QH426-470
Language	English
Publishing date	2021-11-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A New Case of 13q12.2q13.1 Microdeletion Syndrome Contributes to Phenotype Delineation

Giorgia Mandrile / Eleonora Di Gregorio / Alessandro Calcia / Alessandro Brussino / Enrico Grosso / Elisa Savin / Daniela Francesca Giachino / Alfredo Brusco

Case Reports in Genetics, Vol

2014 Volume 2014

Keywords	Genetics ; QH426-470 ; Biology (General) ; QH301-705.5 ; Science ; Q
Language	English
Publishing date	2014-01-01T00:00:00Z
Publisher	Hindawi Publishing Corporation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Human canonical CD157/Bst1 is an alternatively spliced isoform masking a previously unidentified primate-specific exon included in a novel transcript

Enza Ferrero / Nicola Lo Buono / Simona Morone / Rossella Parrotta / Cecilia Mancini / Alfredo Brusco / Alice Giacomino / Stefania Augeri / Antonio Rosal-Vela / Sonia García-Rodríguez / Mercedes Zubiaur / Jaime Sancho / Alessandra Fiorio Pla / Ada Funaro

Scientific Reports, Vol 7, Iss 1, Pp 1-

2017 Volume 14

Abstract: Abstract CD157/Bst1 is a dual-function receptor and β-NAD+-metabolizing ectoenzyme of the ADP-ribosyl cyclase family. Expressed in human peripheral blood neutrophils and monocytes, CD157 interacts with extracellular matrix components and regulates ... ...

Abstract	Abstract CD157/Bst1 is a dual-function receptor and β-NAD+-metabolizing ectoenzyme of the ADP-ribosyl cyclase family. Expressed in human peripheral blood neutrophils and monocytes, CD157 interacts with extracellular matrix components and regulates leukocyte diapedesis via integrin-mediated signalling in inflammation. CD157 also regulates cell migration and is a marker of adverse prognosis in epithelial ovarian cancer and pleural mesothelioma. One form of CD157 is known to date: the canonical sequence of 318 aa from a 9-exon transcript encoded by BST1 on human chromosome 4. Here we describe a second BST1 transcript, consisting of 10 exons, in human neutrophils. This transcript includes an unreported exon, exon 1b, located between exons 1 and 2 of BST1. Inclusion of exon 1b in frame yields CD157-002, a novel proteoform of 333 aa: exclusion of exon 1b by alternative splicing generates canonical CD157, the dominant proteoform in neutrophils and other tissues analysed here. In comparative functional analyses, both proteoforms were indistinguishable in cell surface localization, specific mAb binding, and behaviour in cell adhesion and migration. However, NAD glycohydrolase activity was detected in canonical CD157 alone. Comparative phylogenetics indicate that exon 1b is a genomic innovation acquired during primate evolution, pointing to the importance of alternative splicing for CD157 function.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2017-11-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: X chromosome dosage and presence of SRY shape sex-specific differences in DNA methylation at an autosomal region in human cells

Bianca Ho / Keelin Greenlaw / Abeer Al Tuwaijri / Sanny Moussette / Francisco Martínez / Elisa Giorgio / Alfredo Brusco / Giovanni Battista Ferrero / Natália D. Linhares / Eugênia R. Valadares / Marta Svartman / Vera M. Kalscheuer / Germán Rodríguez Criado / Catherine Laprise / Celia M. T. Greenwood / Anna K. Naumova

Biology of Sex Differences, Vol 9, Iss 1, Pp 1-

2018 Volume 10

Abstract: Abstract Background Sexual dimorphism in DNA methylation levels is a recurrent epigenetic feature in different human cell types and has been implicated in predisposition to disease, such as psychiatric and autoimmune disorders. To elucidate the genetic ... ...

Abstract	Abstract Background Sexual dimorphism in DNA methylation levels is a recurrent epigenetic feature in different human cell types and has been implicated in predisposition to disease, such as psychiatric and autoimmune disorders. To elucidate the genetic origins of sex-specific DNA methylation, we examined DNA methylation levels in fibroblast cell lines and blood cells from individuals with different combinations of sex chromosome complements and sex phenotypes focusing on a single autosomal region––the differentially methylated region (DMR) in the promoter of the zona pellucida binding protein 2 (ZPBP2) as a reporter. Results Our data show that the presence of the sex determining region Y (SRY) was associated with lower methylation levels, whereas higher X chromosome dosage in the absence of SRY led to an increase in DNA methylation levels at the ZPBP2 DMR. We mapped the X-linked modifier of DNA methylation to the long arm of chromosome X (Xq13-q21) and tested the impact of mutations in the ATRX and RLIM genes, located in this region, on methylation levels. Neither ATRX nor RLIM mutations influenced ZPBP2 methylation in female carriers. Conclusions We conclude that sex-specific methylation differences at the autosomal locus result from interaction between a Y-linked factor SRY and at least one X-linked factor that acts in a dose-dependent manner.
Keywords	DNA methylation ; Sex ; X chromosome ; Y chromosome ; Medicine ; R ; Physiology ; QP1-981
Subject code	570
Language	English
Publishing date	2018-02-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A genome-wide association study with tissue transcriptomics identifies genetic drivers for classic bladder exstrophy

Enrico Mingardo / Glenda Beaman / Philip Grote / Agneta Nordenskjöld / William Newman / Adrian S. Woolf / Markus Eckstein / Alina C. Hilger / Gabriel C. Dworschak / Wolfgang Rösch / Anne-Karolin Ebert / Raimund Stein / Alfredo Brusco / Massimo Di Grazia / Ali Tamer / Federico M. Torres / Jose L. Hernandez / Philipp Erben / Carlo Maj /

Jose M. Olmos / Jose A. Riancho / Carmen Valero / Isabel C. Hostettler / Henry Houlden / David J. Werring / Johannes Schumacher / Jan Gehlen / Ann-Sophie Giel / Benedikt C. Buerfent / Samara Arkani / Elisabeth Åkesson / Emilia Rotstein / Michael Ludwig / Gundela Holmdahl / Elisa Giorgio / Alfredo Berettini / David Keene / Raimondo M. Cervellione / Nina Younsi / Melissa Ortlieb / Josef Oswald / Bernhard Haid / Martin Promm / Claudia Neissner / Karin Hirsch / Maximilian Stehr / Frank-Mattias Schäfer / Eberhard Schmiedeke / Thomas M. Boemers / Iris A. L. M. van Rooij

Communications Biology, Vol 5, Iss 1, Pp 1-

2022 Volume 11

Abstract: A genome-wide association study on classic bladder exstrophy reveals eight genome-wide significant loci, most of which contained genes expressed in embryonic developmental bladder stages. ...

Abstract	A genome-wide association study on classic bladder exstrophy reveals eight genome-wide significant loci, most of which contained genes expressed in embryonic developmental bladder stages.
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-11-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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