Temple syndrome in a patient with variably methylated CpGs at the primary MEG3/DLK1:IG-DMR and severely hypomethylated CpGs at the secondary MEG3:TSS-DMR

Kagami, Masayo; Yanagisawa, Atsuhiro; Ota, Masaho; Matsuoka, Katsuyoshi; Nakamura, Akie; Matsubara, Kazuo; Nakabayashi, Kazuhiko; Takada, Shuji; Fukami, Maki; Ogata, Tsutomu

doi:10.1186/s13148-019-0640-2

Cited by 14 publications

(15 citation statements)

References 22 publications

(45 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Patient 2 with MLID (MLID 2) showed mild hypomethylation of the GNAS - A / B :TSS-DMR besides H19L OM. Patient 3 with MLID (MLID 3) showed mild H19L OM besides hypomethylation of the MEG3 :TSS-DMR, as previously reported ( 18 ). A single patient showed abnormal methylation levels in all examined DMRs due to parthenogenesis.…”

Section: Resultssupporting

confidence: 74%

“…Her BW, BL, and present height were −3.5, −3.4, and −3.3 SDS, respectively. Clinical features of MLID 3 have been reported previously ( 18 ). In brief, she showed 6 NH-CSS items and developmental delay.…”

Section: Resultssupporting

confidence: 54%

“…Of 249 patients with SGA-SS, H19 LOM and UPD(7)mat, which are major genetic causes of SRS, were detected in 58 patients (23.3%), and IDs other than H19 LOM and UPD(7)mat were in 29 patients (11.6%). Twenty patients with IDs other than H19 LOM and UPD(7)mat were previously reported (see Table 1 and Table 2 ) ( 8 , 10 , 11 , 18-20 ). These 249 patients with SGA-SS were classified into the SRS-compatible group (n = 148), non-SRS group (n = 94), and non-SRS with microcephaly group (n = 7).…”

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Role of Imprinting Disorders in Short Children Born SGA and Silver-Russell Syndrome Spectrum

Fuke

Nakamura

Inoue

et al. 2020

The Journal of Clinical Endocrinology &Amp; Metabolism

Self Cite

View full text Add to dashboard Cite

Background (Epi)genetic disorders associated with small-for-gestational-age with short stature (SGA-SS) include imprinting disorders (IDs). Silver-Russell syndrome (SRS) is a representative ID in SGA-SS and has heterogenous (epi)genetic causes. Subjects and Methods To clarify the contribution of IDs to SGA-SS and the molecular and phenotypic spectrum of SRS, we recruited 269 patients with SGA-SS consisting of 103 and 166 patients referred to us for genetic testing for SGA-SS and SRS, respectively. After excluding 20 patients with structural abnormalities detected by comparative genomic hybridization analysis using catalog array, 249 patients were classified into three subgroups based on the Netchine-Harbison clinical scoring system (NH-CSS), SRS diagnostic criteria. We screened various IDs by methylation analysis for differentially methylated regions (DMRs) related to known IDs. We also performed clinical analysis. Results These 249 patients with SGA-SS were classified into ‘SRS-compatible group’ (n=148), ‘non-SRS with normocephaly or relative macrocephaly at birth group’ (non-SRS group) (n=94), or ‘non-SRS with relative microcephaly at birth group’ (non-SRS with microcephaly group) (n=7). The 44.6% of patients in ‘SRS-compatible group’, 21.3% of patients in ‘non-SRS group’, and 14.3% in ‘non-SRS with microcephaly group’ had various IDs. Loss of methylation of the H19/IGF2:intergenic-DMR and uniparental disomy chromosome 7, being major genetic causes of SRS, were detected in 30.4% of patients in ‘SRS-compatible group’ and in 13.8% of patients in ‘non-SRS group’. Conclusion We clarified the contribution of IDs as (epi)genetic causes of SGA-SS and the molecular and phenotypic spectrum of SRS. Various IDs constitute underlying factors for SGA-SS, including SRS.

show abstract

Section: Resultssupporting

confidence: 74%

Section: Resultssupporting

confidence: 54%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Role of Imprinting Disorders in Short Children Born SGA and Silver-Russell Syndrome Spectrum

Fuke

Nakamura

Inoue

et al. 2020

The Journal of Clinical Endocrinology &Amp; Metabolism

Self Cite

View full text Add to dashboard Cite

show abstract

“…The mice we generated in this study can provide new insights into regulatory mechanisms involved in IG-DMR-mediated imprinted expression in the human DLK1 - DIO3 domain. In patients with Temple syndrome, epimutation cases involving IG-DMR or MEG3 -DMR, the causes of which are unknown, have been reported ( 29 ). Our results may contribute to an improved understanding of the pathogenesis of these cases.…”

Section: Discussionmentioning

confidence: 99%

Humanization of a tandem repeat in IG-DMR causes stochastic restoration of paternal imprinting at mouseDlk1-Dio3domain

Hara

Terao

Tsuji‐Hosokawa

et al. 2021

Human Molecular Genetics

Self Cite

View full text Add to dashboard Cite

The Dlk1-Dio3 imprinted domain, regulated by an intergenic differentially methylated region (IG-DMR), is important for mammalian embryonic development. Although previous studies have reported that DNA methylation of a tandem repeated array sequence in paternal IG-DMR (IG-DMR-Rep) plays an essential role in the maintenance of DNA methylation in mice, the function of a tandem repeated array sequence in human IG-DMR (hRep) is unknown. Here, we generated mice with a human tandem repeated sequence, which replaced the mouse IG-DMR-Rep. Mice that transmitted the humanized allele paternally exhibited variable methylation status at the IG-DMR and were stochastically rescued from the lethality of IG-DMR-Rep deficiency, suggesting that hRep plays a role in human IG-DMR for the regulation of imprinted expression. Moreover, ChIP analysis showed that TRIM28 was enriched in hypermethylated paternal hRep without ZFP57. Our results suggest that hRep contributes to the maintenance of human IG-DMR methylation imprints via the recruitment of TRIM28.

show abstract

“…We first examined SRS-related underlying factors. The methods utilized in this study were as described previously [14]. Array comparative genomic hybridization using a catalog human array (1 × 1M format, ID G4447A) (Agilent Technologies, CA, USA) showed neither pathogenic nor significance-unknown copy-number variant.…”

Section: Molecular Studiesmentioning

confidence: 99%

Insulin resistant diabetes mellitus in SHORT syndrome: case report and literature review

et al. 2021

Self Cite

View full text Add to dashboard Cite

SHORT syndrome is a rare developmental disorder frequently associated with growth failure and insulin resistant diabetes mellitus (IRDM). Since GH has a diabetogenic effect, GH therapy has been regarded as a contraindication. We observed a Brazilian girl with SHORT syndrome who received GH therapy from 4 6/12 years of age for SGA short stature. GH dosage was increased from 0.23 to 0.36 mg/kg/week, but statural response to GH therapy remained poor. Her blood HbA1c level, though it remained 5.5-6.0% in childhood, began to elevate with puberty and increased to 9.2% at 10 6/12 years of age, despite the discontinuation of GH therapy at 9 11/12 years of age. Laboratory studies indicated antibody-negative IRDM. She was treated with metformin and canagliflozin (a sodium glucose co-transporter 2 (SGLT2) inhibitor), which ameliorated overt diurnal hyperglycemia and mild nocturnal hypoglycemia and reduced her blood HbA1c around 7%. Whole exome sequencing revealed a de novo heterozygous pathogenic variant (c.1945C>T:p.(Arg649Trp)) in PIK3R1 known as the sole causative gene for SHORT syndrome. Subsequent literature review for patients with molecularly confirmed SHORT syndrome revealed the development of IRDM in 10 of 15 GH-untreated patients aged ≥12 years but in none of three GHtreated and six GH-untreated patients aged ≤10 years. These findings imply a critical role of pubertal development and/or advanced age rather than GH therapy in the development of IRDM, and a usefulness of SGLT2 inhibitor in the treatment of IRDM.

show abstract

Temple syndrome in a patient with variably methylated CpGs at the primary MEG3/DLK1:IG-DMR and severely hypomethylated CpGs at the secondary MEG3:TSS-DMR

Cited by 14 publications

References 22 publications

Role of Imprinting Disorders in Short Children Born SGA and Silver-Russell Syndrome Spectrum

Role of Imprinting Disorders in Short Children Born SGA and Silver-Russell Syndrome Spectrum

Humanization of a tandem repeat in IG-DMR causes stochastic restoration of paternal imprinting at mouseDlk1-Dio3domain

Insulin resistant diabetes mellitus in SHORT syndrome: case report and literature review

Contact Info

Product

Resources

About