Bi-allelic loss-of-function variants in TMEM147 cause moderate to profound intellectual disability with facial dysmorphism and pseudo-Pelger-Huët anomaly

Quentin, Thomas; Motta, Marialetizia; Gautier, Thierry; Zaki, Maha S.; Ciolfi, Andrea; Paccaud, Julien; Girodon, François; Boespflug‐Tanguy, Odile; Besnard, Thomas; Kerkhof, Jennifer; McConkey, Haley; Masson, Aymeric; Wieczorek, Dagmar; Cogné, Benjamin; Trochu, Eva; Vignard, Virginie; It, Fatima El; Rodan, Lance H.; Alkhateeb, Mohammad Ayman; Jamra, Rami Abou; Duplomb, Laurence; Tisserant, Émilie; Duffourd, Yannis; Bruel, Ange‐Line; Jackson, Adam; Banka, Siddharth; McEntagart, Meriel; Saggar, Anand; Gleeson, Joseph G.; Sievert, David; Bae, Hyunwoo; Lee, Beom Hee; Kwon, Kisang; Seo, Go Hun; Lee, Hane; Saeed, Anjum; Anjum, Nadeem; Cheema, Huma Arshad; Alawbathani, Salem; Khan, Imran Ali; Pinto‐Basto, Jorge; Teoh, Joyce; Wong, Jasmine C.; Sahari, Umar Bin Mohamad; Houlden, Henry; Zhelcheska, Kristina; Pannetier, Mélanie; Awad, Mona; Lesieur-Sebellin, Marion; Barcia, Giulia; Amiel, Jeanne; Delanne, Julian; Philippe, Christophe; Faivre, Laurence; Odent, Sylvie; Bertoli‐Avella, Aida M.; Thauvin, Christel; Sadiković, Bekim; Reversade, Bruno; Maroofian, Reza; Govin, Jérôme; Tartaglia, Marco; Vitobello, Antonio

doi:10.1016/j.ajhg.2022.08.008

Cited by 7 publications

(6 citation statements)

References 56 publications

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“…All these variants occurred de novo but the TMEM147 variants followed a recessive mode of inheritance. Furthermore, TMEM147 was initially identified as a new candidate gene, and data sharing and functional studies allowed us to confirm its causal role ( Thomas et al, 2022 ).…”

Section: Resultsmentioning

confidence: 99%

OMIXCARE: OMICS technologies solved about 33% of the patients with heterogeneous rare neuro-developmental disorders and negative exome sequencing results and identified 13% additional candidate variants

Colin

Duffourd²,

Tisserant³

et al. 2022

Front. Cell Dev. Biol.

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Purpose: Patients with rare or ultra-rare genetic diseases, which affect 350 million people worldwide, may experience a diagnostic odyssey. High-throughput sequencing leads to an etiological diagnosis in up to 50% of individuals with heterogeneous neurodevelopmental or malformation disorders. There is a growing interest in additional omics technologies in translational research settings to examine the remaining unsolved cases.Methods: We gathered 30 individuals with malformation syndromes and/or severe neurodevelopmental disorders with negative trio exome sequencing and array comparative genomic hybridization results through a multicenter project. We applied short-read genome sequencing, total RNA sequencing, and DNA methylation analysis, in that order, as complementary translational research tools for a molecular diagnosis.Results: The cohort was mainly composed of pediatric individuals with a median age of 13.7 years (4 years and 6 months to 35 years and 1 month). Genome sequencing alone identified at least one variant with a high level of evidence of pathogenicity in 8/30 individuals (26.7%) and at least a candidate disease-causing variant in 7/30 other individuals (23.3%). RNA-seq data in 23 individuals allowed two additional individuals (8.7%) to be diagnosed, confirming the implication of two pathogenic variants (8.7%), and excluding one candidate variant (4.3%). Finally, DNA methylation analysis confirmed one diagnosis identified by genome sequencing (Kabuki syndrome) and identified an episignature compatible with a BAFopathy in a patient with a clinical diagnosis of Coffin-Siris with negative genome and RNA-seq results in blood.Conclusion: Overall, our integrated genome, transcriptome, and DNA methylation analysis solved 10/30 (33.3%) cases and identified a strong candidate gene in 4/30 (13.3%) of the patients with rare neurodevelopmental disorders and negative exome sequencing results.

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Section: Resultsmentioning

confidence: 99%

OMIXCARE: OMICS technologies solved about 33% of the patients with heterogeneous rare neuro-developmental disorders and negative exome sequencing results and identified 13% additional candidate variants

Colin

Duffourd²,

Tisserant³

et al. 2022

Front. Cell Dev. Biol.

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“…TMEM147 has a molecular mass of 25 kDa and predominantly localizes to the ER membrane and the nuclear envelope. Moreover, TMEM147 is an integral component of the nicalin-TMEM147-NOMO protein complex. , Based on published studies, dysregulation of TMEM147 expression may contribute to the pathogenesis of various diseases via diverse mechanisms. A clinical study demonstrated that TMEM147 deficiency leads to the upregulation of CKAP4 (CLIMP-63) and RTN4 (NOGO), accompanied by ER redirection.…”

Section: Introductionmentioning

confidence: 99%

“…Children with TMEM147 deficiency present consistent clinical features, such as coarse facial features, developmental delays, intellectual disability, and behavioral problems. These findings suggest that biallelic loss-of-function TMEM147 variants cause syndromic intellectual disability, ER translocations, and nuclear tissue dysfunction . TMEM147 is a membrane receptor that interacts with galactose lectin, thereby influencing both host innate immune responses and parasite immune responses by regulating cellular proliferation and phagocytosis.…”

Section: Introductionmentioning

confidence: 99%

TMEM147: A Promising Cancer Biomarker Associated with Immune Cell Infiltration and Prognosis in LIHC─Insights from a Comprehensive Pan-Cancer Genomic Analysis

Li,

Chen,

Zhang

et al. 2024

ACS Omega

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“…13,14 After being identified as a component of the Nicalin-NOMO complex, 15 the multifunctionality of TMEM147 was delineated by RNAi silencing and data mining. 14,16 TMEM147 ablation in Hela cells influences cholesterol biosynthesis and uptake by reducing LBR and DHCR protein levels. 17 Evidence from RA patients and mouse models showed overexpression of TMEM147 in chondrocytes, which served as a scaffold for the NF-κB complex, thence promoting its activation.…”

Section: Introductionmentioning

confidence: 99%

“…TMEM147 is widely expressed across normal tissues or malignant tissues 13,14 . After being identified as a component of the Nicalin‐NOMO complex, 15 the multifunctionality of TMEM147 was delineated by RNAi silencing and data mining 14,16 . TMEM147 ablation in Hela cells influences cholesterol biosynthesis and uptake by reducing LBR and DHCR protein levels 17 .…”

Section: Introductionmentioning

confidence: 99%

Transmembrane protein 147, as a potential Sorafenib target, could expedite cell cycle process and confer adverse prognosis in hepatocellular carcinoma

Ma,

Zhang,

et al. 2023

Molecular Carcinogenesis

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TMEM147 was identified as a core component of ribosome‐bound translocon complex at ER/NE. So far, sparse studies reported its expression profiling and oncological implications in hepatocellular carcinoma (HCC) patients. Here we inspected TMEM147 expression levels in HCC cohorts from public databases and tumor tissues. TMEM147 was augmented at transcriptional levels (p < 0.001) and protein levels in HCC patients. A series of bioinformatics tools implemented in R studio were orchestrated in TCGA‐LIHC to evaluate the prognostic significance, compile relevant gene clusters, and explore the oncological functions and therapy responses. It is suggested that TMEM147 could predict poor clinical outcomes effectively and independently (p < 0.001, HR = 2.231 for overall survival (OS) vs. p = 0.04, HR = 2.296 for disease‐specific survival), and was related to risk factors including advanced histologic tumor grade (p < 0.001), AFP level (p < 0.001) and vascular invasion (p = 0.007). Functional enrichment analyses indicated that TMEM147 was involved in cell cycle, WNT/MAPK signaling pathways and ferroptosis. Expression profiling in HCC cell lines, mouse model, and a clinical trial revealed that TMEM147 was a considerable target and marker for adjuvant therapy in vitro and in vivo. Subsequentially, in vitro wet‐lab experimentation authenticated that TMEM147 would be downregulated by Sorafenib administration in hepatoma cells. Lentivirus‐mediated overexpression of TMEM147 could promote cell cycle progression from S phase into G2/M phase, and enhance cell proliferation, thus attenuating drug efficacy and sensitivity of Sorafenib. Further explorations into TMEM147 may inspire a fresh perspective to predict clinical outcomes and improve therapeutic efficacy for HCC patients.

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Bi-allelic loss-of-function variants in TMEM147 cause moderate to profound intellectual disability with facial dysmorphism and pseudo-Pelger-Huët anomaly

Cited by 7 publications

References 56 publications

OMIXCARE: OMICS technologies solved about 33% of the patients with heterogeneous rare neuro-developmental disorders and negative exome sequencing results and identified 13% additional candidate variants

OMIXCARE: OMICS technologies solved about 33% of the patients with heterogeneous rare neuro-developmental disorders and negative exome sequencing results and identified 13% additional candidate variants

TMEM147: A Promising Cancer Biomarker Associated with Immune Cell Infiltration and Prognosis in LIHC─Insights from a Comprehensive Pan-Cancer Genomic Analysis

Transmembrane protein 147, as a potential Sorafenib target, could expedite cell cycle process and confer adverse prognosis in hepatocellular carcinoma

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