The genomic and clinical landscape of fetal akinesia

Pergande, Matthias; Motameny, Susanne; Özdemir, Özkan; Kreutzer, Mona; Wang, Haicui; Daimagüler, Hülya‐Sevcan; Becker, Kerstin; Karakaya, Mert; Ehrhardt, Harald; Elçioğlu, Nursel; Ostojic, Slavica; Chao, Cho-Ming; Kawalia, Amit; Duman, Özgür; Koy, Anne; Hahn, Andreas; Reimann, Jens; Schoner, Katharina; Schänzer, Anne; Westhoff, Jens H.; Schwaibold, Eva Maria Christina; Cossée, Mireille; Imbert‐Bouteille, Marion; Pein, Harald von; Haliloğlu, Göknur; Topaloǧlu, Haluk; Altmüller, Janine; Nürnberg, Peter; Thiele, Holger; Heller, Raoul; Çırak, Sebahattin

doi:10.1038/s41436-019-0680-1

Cited by 42 publications

(48 citation statements)

References 39 publications

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“…Genotype–phenotype relationships are difficult to establish for GLDN variants, as there are too few reported patients to observe reliable patterns. Further complicating this are the mixed outcomes for some patients with identical variants; the combination of p.Phe476Leu and p.Arg393Lys has been seen in two patients, one that survived the neonatal period and one patient who died shortly after delivery with respiratory failure (Pergande et al, 2020; Wambach et al, 2017). It may be the case that outcomes of GLDN patients may be influenced by genetic modifiers or even by the availability and degree of neonatal care.…”

Section: Discussionmentioning

confidence: 99%

“…The second, c.1178G>A, p.Arg393Lys, was previously described in conjunction with another variant, p.Phe476Leu, in two children from different families with overlapping features including extensive congenital contractures (Table S1). Both of these variants are located in the olfactomedin domain of gliomedin, which is known to mediate the protein's interactions with NrCAM and NF186 at the nodes of Ranvier, and is the site of the variants seen in 10 of the 12 previously reported patient variants (Maluenda et al, 2016; Pergande et al, 2020; Wambach et al, 2017).…”

Section: Identification and Analyses Of Patient Variantsmentioning

confidence: 99%

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The latest FADS: Functional analysis of GLDN patient variants and classification of GLDN‐associated AMC as a type of viable fetal akinesia deformation sequence

Mis

Al‐Ali

et al. 2020

American J of Med Genetics Pt A

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Recessive variants in the GLDN gene, which encodes the gliomedin protein and is involved in nervous system development, have recently been associated with Arthrogryposis Multiplex Congenita (AMC), a heterogenous condition characterized by congenital contractures of more than one joint. Two cohorts of patients with GLDN‐associated AMC have previously been described, evolving the understanding of the condition from lethal to survivable with the provision of significant neonatal support. Here, we describe one additional patient currently living with the syndrome, having one novel variant, p.Leu365Phe, for which we provide functional data supporting its pathogenicity. We additionally provide experimental data for four other previously reported variants lacking functional evidence, including p.Arg393Lys, the second variant present in our patient. We discuss unique and defining clinical features, adding calcium‐related findings which appear to be recurrent in the GLDN cohort. Finally, we compare all previously reported patients and draw new conclusions about scope of illness, with emphasis on the finding of pulmonary hypoplasia, suggesting that AMC secondary to GLDN variants may be best fitted under the umbrella of fetal akinesia deformation sequence (FADS).

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Section: Discussionmentioning

confidence: 99%

Section: Identification and Analyses Of Patient Variantsmentioning

confidence: 99%

The latest FADS: Functional analysis of GLDN patient variants and classification of GLDN‐associated AMC as a type of viable fetal akinesia deformation sequence

Mis

Al‐Ali

et al. 2020

American J of Med Genetics Pt A

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“…in vitro results, which revealed that the Gcn2 KO MEFs neither showed proliferative defects nor decreased Cdk1 and cyclin B1 protein levels, as observed in the Gcn1 ΔRWDBD MEFs (Fig 6). Interestingly, GCN1 mutation in human was recently suggested to lead to fetal akinesia that is characterized by reduced or absent fetal movement, but often associate with multiple abnormalities including intra uterine growth retardation [40]. Although GCN1 protein levels were decreased to approximately 30-40% compared to those of the wild-type MEFs, it is not clear at this point to what extent the decrease in GCN1 protein levels contributes to the phenotypes of Gcn1 ΔRWDBD mice other than the lack of the RWDBD.…”

Section: Plos Geneticsmentioning

confidence: 99%

Ribosome binding protein GCN1 regulates the cell cycle and cell proliferation and is essential for the embryonic development of mice

et al. 2020

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Amino acids exert many biological functions, serving as allosteric regulators and neurotransmitters, as constituents in proteins and as nutrients. GCN2-mediated phosphorylation of eukaryotic initiation factor 2 alpha (elF2α) restores homeostasis in response to amino acid starvation (AAS) through the inhibition of the general translation and upregulation of amino acid biosynthetic enzymes and transporters by activating the translation of Gcn4 and ATF4 in yeast and mammals, respectively. GCN1 is a GCN2-binding protein that possesses an RWD binding domain (RWDBD) in its C-terminus. In yeast, Gcn1 is essential for Gcn2 activation by AAS; however, the roles of GCN1 in mammals need to be established. Here, we revealed a novel role of GCN1 that does not depend on AAS by generating two Gcn1 mutant mouse lines: Gcn1-knockout mice (Gcn1 KO mice (Gcn1-/-)) and RWDBD-deleted mutant mice (Gcn1 ΔRWDBD mice). Both mutant mice showed growth retardation, which was not observed in the Gcn2 KO mice, such that the Gcn1 KO mice died at the intermediate stage of embryonic development because of severe growth retardation, while the Gcn1 ΔRWDBD embryos showed mild growth retardation and died soon after birth, most likely due to respiratory failure. Extension of pregnancy by 24 h through the administration of progesterone to the pregnant mothers rescued the expression of differentiation markers in the lungs and prevented lethality of the Gcn1 ΔRWDBD pups, indicating that perinatal lethality of the Gcn1 ΔRWDBD embryos was due to simple growth retardation. Similar to the yeast Gcn2/ Gcn1 system, AAS-or UV irradiation-induced elF2α phosphorylation was diminished in the Gcn1 ΔRWDBD mouse embryonic fibroblasts (MEFs), suggesting that GCN1 RWDBD is responsible for GCN2 activity. In addition, we found reduced cell proliferation and G2/M arrest accompanying a decrease in Cdk1 and Cyclin B1 in the Gcn1 ΔRWDBD MEFs. Our

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“…Consecutively, whole exome sequencing was performed as previously described (Pergande et al, 2019) (see Supplementary Material).…”

Section: To the Editormentioning

confidence: 99%

Mutation in CEP135 causing primary microcephaly and subcortical heterotopia

Bamborschke

Daimagüler

Hahn

et al. 2020

American J of Med Genetics Pt A

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The genomic and clinical landscape of fetal akinesia

Cited by 42 publications

References 39 publications

The latest FADS: Functional analysis of GLDN patient variants and classification of GLDN‐associated AMC as a type of viable fetal akinesia deformation sequence

The latest FADS: Functional analysis of GLDN patient variants and classification of GLDN‐associated AMC as a type of viable fetal akinesia deformation sequence

Ribosome binding protein GCN1 regulates the cell cycle and cell proliferation and is essential for the embryonic development of mice

Mutation in CEP135 causing primary microcephaly and subcortical heterotopia

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