De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder

Lessel, Davor; Schob, Claudia; Küry, Sébastien; Reijnders, Margot R.F.; Harel, Tamar; Eldomery, Mohammad K.; Coban‐Akdemir, Zeynep; Denecke, Jonas; Edvardson, Simon; Colin, Estelle; Stegmann, Alexander P.A.; Gerkes, Erica H.; Tessarech, Marine; Bonneau, Dominique; Barth, Magalie; Besnard, Thomas; Cogné, Benjamin; Revah‐Politi, Anya; Strom, Tim M.; Rosenfeld, Jill A.; Yang, Yaping; Posey, Jennifer E.; Immken, LaDonna; Oundjian, Nelly Jouayed; Helbig, Ingo; Meeks, Naomi; Zegar, Kelsey; Morton, Jenny; Schieving, Jolanda; Claasen, Ana M.; Huentelman, Matthew J.; Narayanan, Vinodh; Ramsey, Keri; Brunner, Han G.; Elpeleg, Orly; Mercier, Sandra; Bézieau, Stéphane; Kubisch, Christian; Kleefstra, Tjitske; Kindler, Stefan; Lupski, James R.; Kreienkamp, Hans‐Jürgen

doi:10.1016/j.ajhg.2017.09.014

Cited by 76 publications

(118 citation statements)

References 41 publications

Supporting

Mentioning

104

Contrasting

Order By: Relevance

“…Using a cutoff of ≥10 peptides, 333 proteins were condensed by r(G4C2)4 as compared with 196 condensed by b-isox (Fig 3B). 19 of the top 25 r(G4C2)4 identified proteins/protein complexes have been previously identified as RNA granule components (Fig 3C, (Kato et al, 2012; Lessel et al, 2017; Wen et al, 2010)). Gene ontology term analysis of r(G4C2)4 condensed proteins indicates an enrichment in RNA processing, (Fig 3D).…”

Section: Resultsmentioning

confidence: 97%

ALS/FTD-Associated C9ORF72 Repeat RNA Promotes Phase Transitions In Vitro and in Cells

2017

View full text Add to dashboard Cite

Summary Membraneless RNA granules originate via phase separation events driven by multivalent interactions. As RNA is the defining component of such granules, we examined how RNA contributes to granule assembly. Expansion of hexanucleotide GGGGCC (G4C2) repeats in the first intron of C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). We describe a biophysical phenomenon whereby G4C2 RNA (rG4C2) promotes the phase separation of RNA granule proteins in vitro and in cells. The ability of rG4C2 to promote phase separation is dependent on repeat length and RNA structure, as rG4C2 must assume a G-quadruplex conformation to promote granule assembly. We demonstrate a central role for RNA in promoting phase separations and implicate rG4C2 G-quadruplex structures in the pathogenesis of C9-ALS/FTD.

show abstract

Section: Resultsmentioning

confidence: 97%

ALS/FTD-Associated C9ORF72 Repeat RNA Promotes Phase Transitions In Vitro and in Cells

2017

View full text Add to dashboard Cite

show abstract

“…There are six superfamilies of RH known with more than 50 human members in superfamily two that are characterized by a DExH and DExD signature in their Walker B motifs, thus termed DHX and DDX proteins. Genetic studies have begun to address the role of altered RH function in human disease (e.g., DHX37 and DHX30 ) 16, 1718, 19.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic expansion in DDX3X – a common cause of intellectual disability in females

Wang

Posey

Rosenfeld

et al. 2018

Ann Clin Transl Neurol

Self Cite

127

View full text Add to dashboard Cite

De novo variants in DDX3X account for 1–3% of unexplained intellectual disability (ID) cases and are amongst the most common causes of ID especially in females. Forty‐seven patients (44 females, 3 males) have been described. We identified 31 additional individuals carrying 29 unique DDX3X variants, including 30 postnatal individuals with complex clinical presentations of developmental delay or ID, and one fetus with abnormal ultrasound findings. Rare or novel phenotypes observed include respiratory problems, congenital heart disease, skeletal muscle mitochondrial DNA depletion, and late‐onset neurologic decline. Our findings expand the spectrum of DNA variants and phenotypes associated with DDX3X disorders.

show abstract

“…Three variants identified in the present study are located in two highly conserved domains, the Helicase ATP-binding, which is a region associated with RNA-binding activity of the RNA helicases, and the Helicase superfamily c-terminal domain, associated with ATPase activity 9 .…”

Section: Discussionmentioning

confidence: 89%

DEAH-box helicase 37 (DHX37) defects are a novel molecular etiology of 46,XY gonadal dysgenesis spectrum

Silva

Gomes

Lerário

et al. 2018

Preprint

View full text Add to dashboard Cite

46, XY gonadal dysgenesis is a heterogeneous disorder of sex development (DSD) that features abnormal gonadal development and varying degrees of undervirilization of the external genitalia, ranging from micropenis to female-like genitalia. Embryonic testicular regression syndrome (ETRS; MIM: 273250) is considered part of the clinical spectrum of 46,XY gonadal dysgenesis. Most ETRS patients present micropenis or atypical genitalia associated with a complete absence of gonadal tissue in one or both sides. In most patients with gonadal dysgenesis, the genetic diagnosis is unclear. We performed whole exome sequencing in ETRS patients and identified a rare variant, the p.Arg308Gln, in DEAH (Asp-Glu-Ala-His) box polypeptide 37 (DHX37) in 5 affected individuals from three unrelated families. We expanded the analysis of DHX37 coding region to additional 71 patients with 46,XY gonadal dysgenesis and identified the p.Arg308Gln and three other DHX37 missense variants (p.Arg151Trp, p.Thr304Met and p.Arg674Trp) in 11 affected members from eight distinct families (8 patients with ETRS, two with partial gonadal dysgenesis and one 46,XY DSD female patient previously gonadectomized). The p.Arg308Gln and p.Arg674Trp recurrent variants were identified in six and three families, respectively. Segregation analysis revealed sex-limited autosomal dominant inheritance in 4 families, autosomal dominant with incomplete penetrance in one family and autosomal recessive in another family. Immunohistochemical analysis of normal testes revealed that DHX37 is expressed in germ cells at different stages of maturation.This study demonstrates an expressive frequency of rare predicted to be deleterious DHX37 variants in 46,XY gonadal dysgenesis group, particularly those individuals exhibiting the ETRS phenotype (25% and 50%, respectively).

show abstract

De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder

Cited by 76 publications

References 41 publications

ALS/FTD-Associated C9ORF72 Repeat RNA Promotes Phase Transitions In Vitro and in Cells

ALS/FTD-Associated C9ORF72 Repeat RNA Promotes Phase Transitions In Vitro and in Cells

Phenotypic expansion in DDX3X – a common cause of intellectual disability in females

DEAH-box helicase 37 (DHX37) defects are a novel molecular etiology of 46,XY gonadal dysgenesis spectrum

Contact Info

Product

Resources

About