Novel de novo mutations in <i>ZBTB20</i> in Primrose syndrome with congenital hypothyroidism

Mattioli, Francesca; Piton, Amélie; Gérard, Bénédicte; Superti‐Furga, Andrea; Mandel, Jean‐Louis; Unger, Sheila

doi:10.1002/ajmg.a.37645

Cited by 29 publications

(32 citation statements)

References 12 publications

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“…Zbtb20 is a member of the BTB/POZ family of transcriptional repressors and functions primarily as a transcriptional repressor ( Xie et al , 2008); it is important for hippocampal development and function, the site of greatest Aβ deposition in aging J20 animals ( Mucke et al , 2000). Moreover, missense mutations in this gene are associated with Primrose syndrome, a cause of intellectual disability with autism ( Cordeddu et al , 2014; Mattioli et al , 2016). Additionally, haploinsufficiency of the gene has been suggested as an important factor in del3q13.31 syndrome, a cause of developmental delay and intellectual disability ( Rasmussen et al , 2014).…”

Section: Resultsmentioning

confidence: 99%

The integration site of the APP transgene in the J20 mouse model of Alzheimer’s disease

Tosh¹,

Rickman²,

Rhymes³

et al. 2017

Wellcome Open Res

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Background: Transgenic animal models are a widely used and powerful tool to investigate human disease and develop therapeutic interventions. Making a transgenic mouse involves random integration of exogenous DNA into the host genome that can have the effect of disrupting endogenous gene expression. The J20 mouse model of Alzheimer’s disease (AD) is a transgenic overexpresser of human APP with familial AD mutations and has been extensively utilised in preclinical studies and our aim was to determine the genomic location of the J20 transgene insertion. Methods: We used a combination of breeding strategy and Targeted Locus Amplification with deep sequencing to identify the insertion site of the J20 transgene array. To assess RNA and protein expression of Zbtb20, we used qRT-PCR and Western Blotting. Results: We demonstrate that the J20 transgene construct has inserted within the genetic locus of endogenous mouse gene Zbtb20 on chromosome 16 in an array , disrupting expression of mRNA from this gene in adult hippocampal tissue, while expression of Zbtb20 protein remains unchanged. We note that the endogenous mouse App gene also lies on chromosome 16, although 42 Mb from the Zbtb20 locus. Conclusions: These data will be useful for future studies utilising this popular model of AD, particularly those investigating gene interactions between the J20 APP transgene and other genes present on Mmu16 in the mouse.

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Section: Resultsmentioning

confidence: 99%

The integration site of the APP transgene in the J20 mouse model of Alzheimer’s disease

Tosh¹,

Rickman²,

Rhymes³

et al. 2017

Wellcome Open Res

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“…Strikingly, the missense variants in the YY1 gene that cause intellectual disability, also appear to cluster in the zinc finger domains, with different variants affecting the identical amino acid residue (Gabriele et al., ). Mutational clustering in the ZNF region is described for ZBTB20 (OMIM# 606025) as well, where de novo variants in the C2H2 ZNF domain of this protein lead to a hypothyroidism phenotype (Mattioli et al., ). In ZBTB42 (OMIM# 613915), a p.Arg>His in one of its C2H2 ZNF domains causes a lethal congenital contracture syndrome (Patel et al., ).…”

Section: Discussionmentioning

confidence: 99%

Toward clinical and molecular understanding of pathogenic variants in the ZBTB18 gene

Schoot

Munnik

Venselaar

et al. 2018

Molec Gen & Gen Med

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BackgroundPatients with pathogenic variants in ZBTB18 present with Intellectual Disability (ID) with frequent co‐occurrence of corpus callosum (CC) anomalies, hypotonia, microcephaly, growth problems and variable facial dysmorphologies. These features illustrate a key role for ZBTB18 in brain development.MethodsPatients with a pathogenic variant in ZBTB18 were detected by diagnostic whole exome sequencing (WES) performed in our center. We reviewed the literature and used GeneMatcher to include other cases. YASARA and WHAT IF were used to provide insight into the structural effect of missense variants located in the C2H2 zinc finger domains of the ZBTB18 protein.ResultsWe give a complete overview of pathogenic variants in ZBTB18 detected to date, showing inconsistent presence of clinical features, including CC anomalies. We present four new cases with a de novo pathogenic variant in the ZBTB18 gene, including the fourth case in which a de novo p.Arg464His variant was found.ConclusionHomology modeling of protein structure points to a variable degree of impaired DNA binding caused by missense variants in these domains probably leading to Loss of Function (LoF). Putative partial LoF may present with a less distinctive phenotype than complete LoF, as seen in truncating variants, which presents with an extensive variability in the phenotypic spectrum. Our data do not support a clear genotype to phenotype correlation.

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“…A ZBTB20 disruption due to a de novo balanced translocation has also been identified in a patient with similar clinical features (Rasmussen et al, ). Finally, in 2014, de novo mutations in ZBTB20 were identified in patients presenting clinical features of Primrose syndrome (Cordeddu et al, ) and additional patients with ZBTB20 mutations have been reported to date (Alby et al, ; Casertano et al, ; Cleaver et al, ; Grimsdottir et al, ; Mattioli et al, ; Stellacci et al, ). Thus, ZBTB20 was established as a gene responsible for Primrose syndrome and 3q13.31 deletion syndrome.…”

Section: Introductionmentioning

confidence: 99%

Primrose syndrome associated with unclassified immunodeficiency and a novel ZBTB20 mutation

Yamamoto-Shimojima

Imaizumi

Akagawa

et al. 2019

American J of Med Genetics Pt A

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Primrose syndrome is a congenital malformation syndrome characterized by intellectual disability, developmental delay, progressive muscle wasting, and ear lobe calcification. Mutations in the ZBTB20 gene have been established as being accountable for this syndrome. In this study, a novel de novo ZBTB20 mutation, NM_001164342.2:c.1945C>T (p.Leu649Phe), has been identified through whole exome sequencing (WES) in a female patient presenting a typical Primrose phenotype. Because the present patient exhibited recurrent otitis media, detailed immunological examinations were performed in this study and subnormal immunoglobulin levels were firstly identified in a Primrose patient. Anatomical anomaly of the inner ear has never been reported in this patient and WES data did not include any relevant variants causally linked with the immunologic defect. Thus, there is a possibility of a relation between an unclassified immunodeficiency with selective IgG2 deficiency and Primrose syndrome and this may be the reason of recurrent otitis media frequently observed in Primrose patients. Because subnormal levels of IgG2 in this patient might be caused by an unrelated and still uncharacterized genetic cause, further studies are required to prove the causal link between aberrant ZBTB20 function and immunodeficiency.

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Novel de novo mutations in ZBTB20 in Primrose syndrome with congenital hypothyroidism

Cited by 29 publications

References 12 publications

The integration site of the APP transgene in the J20 mouse model of Alzheimer’s disease

The integration site of the APP transgene in the J20 mouse model of Alzheimer’s disease

Toward clinical and molecular understanding of pathogenic variants in the ZBTB18 gene

Primrose syndrome associated with unclassified immunodeficiency and a novel ZBTB20 mutation

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