Rare EIF4A2 variants are associated with a neurodevelopmental disorder characterized by intellectual disability, hypotonia, and epilepsy

Paul, Maimuna Sali; Duncan, Anna R.; Genetti, Casie A.; Pan, Hongling; Jackson, Adam; Grant, P. Ellen; Shi, Jiahai; Pinelli, Michele; Brunetti‐Pierri, Nicola; Garza-Flores, Alexandra; Shahani, Dave; Saneto, Russell P.; Zampino, Giuseppe; Leoni, Chiara; Agolini, Emanuele; Novelli, Antonio; Blümlein, Ulrike; Haack, Tobias B.; Heinritz, Wolfram; Matzker, Eva; Alhaddad, Bader; Jamra, Rami Abou; Bartolomaeus, Tobias; AlHamdan, Saber; Carapito, Raphaël; Isidor, Bertrand; Bahram, Seiamak; Ritter, Alyssa; Izumi, Kosuke; Shakked, Ben Pode; Barel, Ortal; Zeev, Bruria Ben; Begtrup, Amber; Carere, Deanna Alexis; Mullegama, Sureni V; Palculict, Timothy Blake; Calame, Daniel G.; Schwan, Katharina; Aycinena, Alicia R. P.; Traberg, Rasa; Douzgou, Sofia; Pirt, Harrison; Ismayilova, Naila; Banka, Siddharth; Chao, Hsiao‐Tuan; Agrawal, Pankaj B.

doi:10.1016/j.ajhg.2022.11.011

Cited by 10 publications

(25 citation statements)

References 51 publications

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“…Functionally important protein regions are illustrated: the Q motif, the helicase ATP-binding domain, and the helicase C-terminal domain. Locations of herein identified and previously reported 18,28,29 variants are shown at the cDNA (upper panel) and the protein (lower panel) level. The dystonia-associated variants observed in families A-D are plotted above and variants described in patients with neurodevelopmental disease syndromes 18,28,29 below the gene/protein.…”

Section: Genetics Datamentioning

confidence: 99%

“…Locations of herein identified and previously reported 18,28,29 variants are shown at the cDNA (upper panel) and the protein (lower panel) level. The dystonia-associated variants observed in families A-D are plotted above and variants described in patients with neurodevelopmental disease syndromes 18,28,29 below the gene/protein. Variants depicted in blue, green, and black represent loss of function (frameshift), in-frame deletion, and missense changes, respectively.…”

Section: Genetics Datamentioning

confidence: 99%

“…Variants depicted in blue, green, and black represent loss of function (frameshift), in-frame deletion, and missense changes, respectively. All literature-reported variants were heterozygous de novo mutations, except for three biallelic variants that are marked with boxes; a newly acquired, previously undescribed fibroblast line established from a compound heterozygous carrier of c.186_187del (p.Arg62Serfs*7) and c.1161_1166del (p.Asp387_Ile388del) 18 Slovak family (family A, patient A-II-4 was part of the primary analysis cohort; see Subjects and Methods) and a mother-son pair of German descent (family B, patient B-III-2 from the primary analysis cohort; see Subjects and Methods). These patients' exomes contained no alternative rare variants considered to be responsible for their dystonic phenotypes.…”

Section: Genetics Datamentioning

confidence: 99%

“…15,17 Recently, variants in another component of the protein synthetic pathway, eukaryotic translation initiation factor 4A isoform 2 (eIF4A2, encoded by EIF4A2), were found to lead to neurodevelopmental disorders with developmental delay, intellectual disability, and epilepsy. 18 Especially de novo missense and deletion mutations (besides biallelic variants in two recessive pedigrees) were described, many of which were demonstrated to induce heterozygous loss of eIF4A2 function. 18 To date, no movement disorders have been reported with variants in EIF4A2.…”

Section: Introductionmentioning

confidence: 99%

“…18 Especially de novo missense and deletion mutations (besides biallelic variants in two recessive pedigrees) were described, many of which were demonstrated to induce heterozygous loss of eIF4A2 function. 18 To date, no movement disorders have been reported with variants in EIF4A2. In this study, we mined large-scale genomic datasets of patients with dystonia 19,20 to identify two independent families with multiple affected individuals who segregated an identical unique frameshift EIF4A2 variant.…”

Section: Introductionmentioning

confidence: 99%

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Dystonia Linked to EIF4A2 Haploinsufficiency: A Disorder of Protein Translation Dysfunction

Harrer

Škorvánek²,

Kittke

et al. 2023

Movement Disorders

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BackgroundProtein synthesis is a tightly controlled process, involving a host of translation‐initiation factors and microRNA‐associated repressors. Variants in the translational regulator EIF2AK2 were first linked to neurodevelopmental‐delay phenotypes, followed by their implication in dystonia. Recently, de novo variants in EIF4A2, encoding eukaryotic translation initiation factor 4A isoform 2 (eIF4A2), have been described in pediatric cases with developmental delay and intellectual disability.ObjectiveWe sought to characterize the role of EIF4A2 variants in dystonic conditions.MethodsWe undertook an unbiased search for likely deleterious variants in mutation‐constrained genes among 1100 families studied with dystonia. Independent cohorts were screened for EIF4A2 variants. Western blotting and immunocytochemical studies were performed in patient‐derived fibroblasts.ResultsWe report the discovery of a novel heterozygous EIF4A2 frameshift deletion (c.896_897del) in seven patients from two unrelated families. The disease was characterized by adolescence‐ to adulthood‐onset dystonia with tremor. In patient‐derived fibroblasts, eIF4A2 production amounted to only 50% of the normal quantity. Reduction of eIF4A2 was associated with abnormally increased levels of IMP1, a target of Ccr4‐Not, the complex that interacts with eIF4A2 to mediate microRNA‐dependent translational repression. By complementing the analyses with fibroblasts bearing EIF4A2 biallelic mutations, we established a correlation between IMP1 expression alterations and eIF4A2 functional dosage. Moreover, eIF4A2 and Ccr4‐Not displayed significantly diminished colocalization in dystonia patient cells. Review of international databases identified EIF4A2 deletion variants (c.470_472del, c.1144_1145del) in another two dystonia‐affected pedigrees.ConclusionsOur findings demonstrate that EIF4A2 haploinsufficiency underlies a previously unrecognized dominant dystonia‐tremor syndrome. The data imply that translational deregulation is more broadly linked to both early neurodevelopmental phenotypes and later‐onset dystonic conditions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Section: Genetics Datamentioning

confidence: 99%

Section: Genetics Datamentioning

confidence: 99%

Section: Genetics Datamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dystonia Linked to EIF4A2 Haploinsufficiency: A Disorder of Protein Translation Dysfunction

Harrer

Škorvánek²,

Kittke

et al. 2023

Movement Disorders

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Expansion of clinical and variant spectrum of EEF2‐related neurodevelopmental disorder: Report of two additional cases

Guo

Rippert

Cook

et al. 2023

American J of Med Genetics Pt A

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Eukaryotic translation elongation factor 2 (eEF2), encoded by the gene EEF2, is an essential factor involved in the elongation phase of protein translation. A specific heterozygous missense variant (p.P596H) in EEF2 was originally identified in association with autosomal dominant adult‐onset spinocerebellar ataxia‐26 (SCA26). More recently, additional heterozygous missense variants in this gene have been described to cause a novel, childhood‐onset neurodevelopmental disorder with benign external hydrocephalus. Herein, we report two unrelated individuals with a similar gene‐disease correlation to support this latter observation. Patient 1 is a 7‐year‐old male with a previously reported, de novo missense variant (p.V28M) who has motor and speech delay, autism spectrum disorder, failure to thrive with relative macrocephaly, unilateral microphthalmia with coloboma and eczema. Patient 2 is a 4‐year‐old female with a novel de novo nonsense variant (p.Q145X) with motor and speech delay, hypotonia, macrocephaly with benign ventricular enlargement, and keratosis pilaris. These additional cases help to further expand the genotypic and phenotypic spectrum of this newly described EEF2‐related neurodevelopmental syndrome.

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RNA binding proteins in cardiovascular development and disease

Verma,

Kuyumcu-Martinez

2024

Current Topics in Developmental Biology

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Rare EIF4A2 variants are associated with a neurodevelopmental disorder characterized by intellectual disability, hypotonia, and epilepsy

Cited by 10 publications

References 51 publications

Dystonia Linked to EIF4A2 Haploinsufficiency: A Disorder of Protein Translation Dysfunction

Dystonia Linked to EIF4A2 Haploinsufficiency: A Disorder of Protein Translation Dysfunction

Expansion of clinical and variant spectrum of EEF2‐related neurodevelopmental disorder: Report of two additional cases

RNA binding proteins in cardiovascular development and disease

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