Epoxide hydrolases (EHs) constitute a small protein family, first characterized as a group of detoxifying enzymes (Oesch et al., 1973). The first EHs were identified more than 40 years ago, and, to date, five genes encoding EH have been identified in humans (Decker et al., 2012; Fretland and Omiecinski, 2000). Human microsomal and soluble EHs (mEH and sEH), also named EPHX1 and EPHX2, respectively, are the best known EHs. Structurally, they are alpha/beta hydrolase fold enzymes. They catalyze the rapid hydrolysis of epoxides, which are three membered cyclic ethers, to less-reactive and readily excretable diols (Oesch et al., 1971). In mammals, epoxides arise from cytochrome P450 (CYP450) oxidative metabolism of both xenobiotics and endogenous compounds (El-Sherbeni and El-Kadi, 2014). Epoxides from xenobiotics are involved in the development of cancers and organ damage through interaction with DNA, lipids, and proteins (Nebert and Dalton, 2006), and EHs are necessary for their detoxification. On the other hand, epoxides derived from endogenous fatty acids, called epoxy fatty acids (EpFAs), are important regulatory lipid mediators. They were shown to mediate several biological processes, including inflammation, angiogenesis, vasodilation, and nociception. By regulating EpFAs levels, EHs play a key role in regulating crucial signaling pathways for cellular homeostasis (McReynolds et al., 2020), and altered levels of EpFAs are associated with many disorders (Morisseau and Hammock, 2013). Although a large amount of work has been made to characterize EH functions, especially through the use of specific inhibitors and animal models, the full spectrum of their substrates and associated biological functions in human remain partly unknown (Gautheron and Jéru, 2020). It is also a challenge to clearly define the contribution of each EH in human disorders.

Association studies suggested a role of several single-nucleotide polymorphisms (SNPs) identified in EPHX1 [MIM132810] and EPHX2 [MIM132811] in multiple conditions, including liver cirrhosis, alcohol dependence, Crohn’s disease, chronic obstructive pulmonary disease, preeclampsia, diabetes mellitus, and many cancers (El-Sherbeni and El-Kadi, 2014; Václavíková et al., 2015). This underscores the pleiotropic and crucial role of EHs in cell homeostasis, but no high-effect variants have been reported to date. In the present study, we identified two unrelated patients with a complex lipoatrophic and neurodevelopmental syndrome with severe metabolic manifestations and carrying a de novo variant in EPHX1 identified by whole-exome sequencing (WES). Lipoatrophic diabetes, also known as lipodystrophic syndromes, are characterized by clinical lipoatrophy due to a defect in adipose tissue storage of triglycerides. This results in ectopic lipid infiltration of non-adipose tissues leading to insulin resistance, increased liver glucose production, hypertriglyceridemia, and liver steatosis. About 30 genes have been implicated in lipoatrophic diabetes (Brown et al., 2016). Although these disorders remain genetically unexplained in the vast majority of cases, there is growing interest in identifying their molecular and cellular bases to improve genetic counseling and personalize treatment (Letourneau and Greeley, 2018; Sollier et al., 2020).

EPHX1 is widely expressed with highest expression in the liver, adipose tissue, and adrenal glands (Coller et al., 2001). It was the first mammalian EH to be identified and was first purified from rabbit liver in the 1970s. It is an evolutionarily highly conserved biotransformation enzyme retained in microsomal membranes of the endoplasmic reticulum (ER) (Coller et al., 2001). For a long time, EPHX1 and EPHX2 were thought to simply fulfill distinct complementary roles (Decker et al., 2009). On the one hand, EPHX1 was well recognized to detoxify xenobiotic epoxides. On the other hand, EPHX2 was shown to hydrolyze endogenous terpenoid epoxides and EpFAs (El-Sherbeni and El-Kadi, 2014). More recently, EPHX1 was also shown in animal models to play a significant role in the hydrolysis of different endogenous EpFAs derived from polyunsaturated fatty acids (Edin et al., 2018; Snider et al., 2007; Marowsky et al., 2017; Blum et al., 2019). These EpFAs, including epoxyeicosatrienoic acids (EETs) and epoxyoctadecenoic acids (also called EpOMEs), are formed by ER-attached CYP450s and hydrolyzed by EPHX1 to their respective diols, the so-called dihydroxyeicosatrienoic acids (DHETs) and dihydroxyoctadecenoic acids (DiHOMEs), respectively. Nevertheless, from an evolutionary perspective, EPHX1 and EPHX2 are very different enzymes, which can be differentially inhibited by distinct chemical inhibitors, and display only a partially overlapping substrate selectivity.

The EPHX1 variants identified in the studied patients are localized in the catalytic domain of the enzyme and were predicted to be pathogenic. This prompted us to assess their functional consequences in several cellular models. The impact of the loss of EPHX1 activity on adipocyte differentiation and function was evaluated by developing CRISPR-Cas9-mediated genome-editing approaches.

This translational study presents the first example of a monogenic disorder related to a gene in the EH family. The data demonstrate the pleiotropic effect of EPHX1 and its key role in cell homeostasis. This is consistent with the high evolutionary conservation of EHs across multiple organisms, including animals, insects, plants, fungi, and bacteria (van Loo et al., 2006), and underscores their essential biological function.

In this study, two different EPHX1 de novo missense variants were identified in patients with a progressive multisystemic disorder. According to the American College of Medical Genetics and Genomics (ACMG) criteria (Richards et al., 2015), these variants can be classified as ‘pathogenic’ with the inclusion of our functional data. The two patients share a number of clinical characteristics including dysmorphic features and manifestations affecting the liver, adipose tissue, and nervous system. The broad expression of EPHX1 explains how germline variants in this gene result in this multisystemic phenotype. As an example, EPHX1 transcripts have been detected in various areas of the brain (Farin and Omiecinski, 1993), and EPHX1 was also recently shown to play a complementary role to EPHX2 in the brain metabolism of naturally occurring EETs, which constitute a major class of EpFAs (Marowsky et al., 2016; Marowsky et al., 2009). The involvement of the EPHX1 de novo variants identified herein in diabetes and liver dysfunction is also consistent with a number of previous observations. Firstly, the expression of EPHX1 is regulated by various transcriptional factors including GATA4 and HNF4A (Liang et al., 2005; Peng et al., 2013), two genes implicated in other forms of monogenic diabetes. In regard to systemic hormonal regulation, it was demonstrated in primary hepatocytes that insulin positively and glucagon negatively regulate EPHX1 expression (Kim et al., 2003). A previous study also showed that a common polymorphism in EPHX1 (p.Tyr113His) was associated with an increased risk of type 2 diabetes mellitus and insulin resistance (Ghattas and Amer, 2012), as well as liver cirrhosis (Sonzogni et al., 2002). It was shown that EPHX1 plays a key role in the liver metabolism of endogenous lipids (Marowsky et al., 2017). Regarding hormonal pathophysiology, patient 1 developed amenorrhea associated with steroidogenesis alterations. Partial and generalized lipoatrophy are commonly associated with insulin resistance and hyperandrogenism (Joy and Hegele, 2008). Indeed, hyperinsulinemia directly stimulates ovarian androgen production, which in turn alters insulin sensitivity with a positive feedback loop between insulin resistance and hyperandrogenism. The major insulin resistance observed in patient 1 might thus contribute to hyperandrogenism signs. Nevertheless, her total testosterone levels are much higher than those usually observed in lipodystrophic patients (Huang-Doran et al., 2021). Such an elevation of testosterone levels in the absence of tumor and in the presence of normal estradiol levels rather argue for a direct or indirect blockade of the aromatase activity. In this regard, a potential role of EPHX1 in reproductive physiology was suggested previously. EPHX1 is expressed in ovarian follicle cells (Cannady et al., 2002) and is regulated by progesterone during the menstrual cycle (Popp et al., 2010). Several endogenous biologically active epoxide mediators of the steroidogenic pathway were found to be EPHX1 substrates, such as androstene oxide (16α,17α-epoxyandrosten-3-one) and estroxide (epoxyestratrienol) (Vogel-Bindel et al., 1982). EPHX1 protects cells from oxidative stress in oviducts (Cheong et al., 2009). A decrease in estradiol formation from testosterone was seen in human ovaries upon treatment with an EPHX1 inhibitor (Hattori et al., 2000). Polycystic ovary syndrome, characterized by hyperandrogenism and elevated serum testosterone levels, is observed in patients taking sodium valproate (Isojarvi et al., 1993), an anti-epileptic and anti-convulsant drug known to inhibit EPHX1 activity (Kerr et al., 1989). This observation is reminiscent of what is seen in our patient, who displays signs of hyperandrogenism in association with a loss of EPHX1 activity. The role of EPHX1 on the reproductive function could also be illustrated by the reported link between EPHX1 polymorphisms and spontaneous abortion (Wang et al., 1998) or preeclampsia (Laasanen et al., 2002). Consequently, further functional experiments in estrogen-producing granulosa cell models would be helpful to understand how EPHX1 could modulate aromatase activity or other steps of the steroidogenic pathway.

There were few data on the role of EPHX1 in adipose tissue, and its function in adipocytes remained elusive. The current study supports a role for EPHX1 in adipogenesis and adipocyte functions. We observed a defect in adipocyte differentiation in 3T3-L1 cells with CRISPR-Cas9 KO of Ephx1. This cellular model also revealed decreased expression of mature adipocyte markers, as well as altered insulin signaling even in pre-adipocytes. This is consistent with the lipoatrophic phenotype observed in the two patients carrying de novo EPHX1 pathogenic variants. Such an adipocyte differentiation defect has been reported in several other lipoatrophic diabetes of various genetic origins (Akinci et al., 2018a; Capel et al., 2018; Sollier et al., 2021). Lipoatrophic diabetes are indeed characterized by an incapacity of adipose tissue to store triglycerides, leading to ectopic fat depots and insulin resistance. The profound serum leptin and adiponectin deficiency observed in patients further confirms an endocrine defect of adipose tissue, since these hormones are secreted by mature adipocytes. What is the cellular link between the loss of EPHX1 activity and adipogenesis defect? EPHX1 substrates might play a key role since oxylipins, which are EPHX1 substrates, target peroxisome proliferator-activated receptors (PPARs) to modify adipocyte formation and function (Barquissau et al., 2017). It has also been reported that EETs decrease mesenchymal stem cells (MSC)-derived adipocyte differentiation by inhibiting PPARγ, C/EBPα, and FAS (Kim et al., 2010). In addition, PPARγ agonists have been shown to increase the expression of EPHX2 (De Taeye et al., 2010), whose expression is also interdependent of that of EPHX1 (Edin et al., 2018). Additional experiments will be required to precisely define the link between the loss of EPHX1 and adipogenesis alteration, which might involve the deregulation of PPARγ agonists or antagonists. Altogether, these data show that EPHX1, with its crucial role in epoxide reactive species biotransformation, stands at the crossroad of several signaling pathways and thereby plays a key role in cell metabolism and homeostasis.

EpFAs are endogenous lipid mediators functionally regulated in part by their hydrolysis by EPHX1 and EPHX2. Strategies stabilizing or mimicking EpFAs are commonly reported to contribute to cell homeostasis maintenance (Bettaieb et al., 2013; Wang et al., 2014; Liu et al., 2018). In this regard, it has been proposed that EpFAs prevent mitochondrial dysfunction, reduce ROS formation, and alleviate ER stress (Inceoglu et al., 2017). EETs exhibit numerous beneficial effects, such as anti-inflammatory, analgesic, vasodilatory, angiogenic, fibrinolytic, tissue-regenerating, and cytoprotective effects (Marowsky et al., 2017; Imig, 2012; Morisseau, 2013). This has been deeply investigated for EPHX2, and specific inhibitors have shown beneficial effects on a wide range of apparently unrelated conditions, including diabetes, fibrosis, chronic pain, cardiovascular, and neurodegenerative diseases (Ghosh et al., 2020), so that several of these EPHX2 inhibitors were tested in phase I clinical trials (Morisseau and Hammock, 2013; Imig and Hammock, 2009). In contrast, the current study shows that a loss of EPHX1 activity can be associated with a severe multisystemic phenotype. How to reconcile these apparently conflicting data? Like numerous other signaling molecules, the function of EpFAs strongly depend on the biological context (Inceoglu et al., 2017). The absence of a measurable effect of EpFAs under basal conditions is consistently observed across different laboratories and is in stark contrast to their strong efficacy under pathological situations. EpFAs seem to function with fine tuning to regulate and maintain cell homeostasis. This point is best illustrated by the ability of EPHX2 inhibitors to shift both hypertension and hypotension toward normotension in rodent models (Sinal et al., 2000; Ulu et al., 2016).

The gnomAD database, which collects variants from the general population, reports several dozen predicted loss-of-function variants in EPHX1, including nonsense, frameshift, and canonical splice site variants. This suggests that the pathogenic effect of the missense variants identified in patients 1 and 2 is not only due to a loss-of-function, but may be associated with a dominant negative mechanism. A previous study on the 3D-structure of EPHX1 suggests that this enzyme, which is mostly membrane bound, might be dimeric (Zou et al., 2000). This would be in favor of a dominant negative effect, as well as the formation of higher-order complexes within the ER observed in overexpression studies. Although this aspect of EPHX1 structure has so far been poorly explored, it may have important consequences for EPHX1 function, for example, by pre-orienting the enzyme for binding of either substrates or functional partners. We did not detect any dominant negative effect in the c-SO hydrolysis assay when co-expressing WT and mutated forms of EPHX1 (Figure 2—figure supplement 2). However, overexpression studies are probably not the most appropriate system to investigate such properties. Additional studies will be required to better understand EPHX1 activity when embedded in the microsomal ER membranes in endogenous conditions. In any case, the final result is a loss of the enzyme activity, consistent with the localization of the variants at the center of EPHX1 catalytic site. EPHX1 KO in 3T3-L1-pre-adipocytes revealed a high rate of ROS production, an observation confirmed in patient 1-derived fibroblasts. These data reinforce the proposed role of EHs as regulators of oxidative stress (Cheong et al., 2009; Inceoglu et al., 2017; Ulu et al., 2016). Patient 1-derived fibroblasts displayed an altered morphology, senescent features such as an increase in the SA-β-gal marker, as well as a reduced proliferative rate. This senescent phenotype was reproduced by removing EPHX1 in 3T3-L1 pre-adipocytes and ASCs, which subsequently loss their capacity to differentiate into adipocytes. Our findings not only support the notion that cellular senescence is an important player in adipogenesis, but also argue that EPHX1 might directly regulate adipocyte differentiation.

Regarding available animal models, Ephx1 knockout mice have already been generated (Miyata et al., 1999). Deletion of the gene in the heterozygous or homozygous state did not induce an obvious phenotype and histological examination of several organs revealed no difference between Ephx1-null mice and wild-type littermates. The first complexity when attempting to model lipodystrophy in mice is the differences between human and murine fat distribution and lipid metabolism, particularly the handling and oxidation of lipids (Rochford, 2014). So far, it appears that observations made in models of congenital generalized lipodystrophies (CGL) can translate quite accurately from mice to humans. Indeed, the most frequent CGL are autosomal recessive disorders due to bi-allelic null variants. In contrast, familial partial lipodystrophy syndromes are more difficult to study in mice, since they are often autosomal dominant and some variants induce a dominant negative effect (Garg, 2011). Knock-in mice would be required to better investigate such pathophysiological mechanisms for EPHX1 variants, and additional metabolic stress is sometimes needed to uncover more aspects of the human phenotype (Gray et al., 2006).

In this study, we were also interested in improving the therapeutic management of this novel clinical entity, which justifies careful clinical evaluation and requires multidisciplinary care. Patient 1 suffered from very severe diabetes with persistent glycemic imbalance despite very high insulin doses. Metreleptin was shown to reduce hyperphagia leading to weight loss, to improve insulin sensitivity and secretion, to reduce hypertriglyceridemia, hyperglycemia, and fatty liver disease in many patients with lipoatrophic diabetes (Vatier et al., 2016; Akinci et al., 2018b). All these beneficial effects were rapidly observed in patient 1 after treatment initiation. Besides, regarding the specific role of EPHX1 as a xenobiotic detoxifying enzyme, another practical implication of this study for the patient is the contraindication to all drugs known to be metabolized by EPHX1, especially carbamazepine, phenobarbital, and phenytoin (El-Sherbeni and El-Kadi, 2014). They would not be properly metabolized by EPHX1 and eliminated by the patient leading to toxicity.

The data presented here emphasize that lipid mediator regulation by EHs is essential for homeostasis and that its alteration is a newly discovered mechanism in monogenic insulin-resistant lipoatrophic diabetes. The field of monogenic diabetes is quickly advancing, and knowledge gained in recent years led to great improvements in understanding of their molecular and cellular bases. This allows to improve overall quality of life for patients and their families, with earlier diagnoses and personalized treatments. Continued efforts at gene discovery may help reveal mechanistic pathways implicated in the more common forms of type 1 and type 2 diabetes and lead to better treatments and outcomes.

Plasmids used in this study have been deposited in Addgene under accession number 79368. Exome data from human subjects cannot been made available, since the informed written consents did not permit sharing of the full sequence data. To circumvent this fact and to fit with the Editor and Reviewers' comment, two supplementary files have been provided listing all other rare variants identified in the two families investigated herein, according to the corresponding mode of inheritance. For each variant, we indicated the items arguing against its involvement in the disease phenotype. All data generated or analysed during this study are included in the manuscript and supporting files. Source data have been provided for all western blot experiments.

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Author details

1. Jeremie Gautheron

   1. Sorbonne Université-Inserm UMRS_938, Centre de Recherche Saint-Antoine (CRSA), Paris, France
   2. Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France

   Contribution

   Conceptualization, Data curation, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Methodology, Writing - original draft, Project administration, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7727-9893

2. Christophe Morisseau

   Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, Davis, United States

   Contribution

   Data curation, Formal analysis, Funding acquisition, Validation, Investigation, Writing - review and editing

   Competing interests

   No competing interests declared

3. Wendy K Chung

   1. Department of Pediatrics, Columbia University Irving Medical Center, New York, United States
   2. Deparment of Medicine, Columbia University Irving Medical Center, New York, United States

   Contribution

   Data curation, Formal analysis, Funding acquisition, Validation, Investigation, Writing - review and editing

   Competing interests

   No competing interests declared

4. Jamila Zammouri

   1. Sorbonne Université-Inserm UMRS_938, Centre de Recherche Saint-Antoine (CRSA), Paris, France
   2. Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France

   Contribution

   Data curation, Formal analysis, Investigation, Writing - review and editing

   Competing interests

   No competing interests declared

5. Martine Auclair

   1. Sorbonne Université-Inserm UMRS_938, Centre de Recherche Saint-Antoine (CRSA), Paris, France
   2. Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France

   Contribution

   Data curation, Formal analysis, Investigation, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

6. Genevieve Baujat

   Service de Génétique Clinique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France

   Contribution

   Data curation, Formal analysis, Investigation, Writing - review and editing

   Competing interests

   No competing interests declared

7. Emilie Capel

   1. Sorbonne Université-Inserm UMRS_938, Centre de Recherche Saint-Antoine (CRSA), Paris, France
   2. Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France

   Contribution

   Data curation, Formal analysis, Investigation, Writing - review and editing

   Competing interests

   No competing interests declared

8. Celia Moulin

   1. Sorbonne Université-Inserm UMRS_938, Centre de Recherche Saint-Antoine (CRSA), Paris, France
   2. Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France

   Contribution

   Data curation, Formal analysis, Investigation, Writing - review and editing

   Competing interests

   No competing interests declared

9. Yuxin Wang

   Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, Davis, United States

   Contribution

   Data curation, Formal analysis, Investigation, Writing - review and editing

   Competing interests

   No competing interests declared

10. Jun Yang

    Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, Davis, United States

    Contribution

    Data curation, Formal analysis, Investigation, Writing - review and editing

    Competing interests

    No competing interests declared

11. Bruce D Hammock

    Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, Davis, United States

    Contribution

    Data curation, Formal analysis, Writing - review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0003-1408-8317

12. Barbara Cerame

    Goryeb Children’s Hospital, Atlantic Health Systems, Morristown Memorial Hospital, Morristown, United States

    Contribution

    Data curation, Formal analysis, Writing - review and editing

    Competing interests

    No competing interests declared

13. Franck Phan

    1. Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
    2. Service de Diabétologie-Métabolisme, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France
    3. Sorbonne Université-Inserm UMRS_1269, Paris, France

    Contribution

    Data curation, Formal analysis, Writing - review and editing

    Competing interests

    No competing interests declared

14. Bruno Fève

    1. Sorbonne Université-Inserm UMRS_938, Centre de Recherche Saint-Antoine (CRSA), Paris, France
    2. Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
    3. Centre National de Référence des Pathologies Rares de l’Insulino-Sécrétion et de l’Insulino-Sensibilité (PRISIS), Service de Diabétologie et Endocrinologie de la Reproduction, Hôpital Saint-Antoine, AP-HP, Paris, France

    Contribution

    Conceptualization, Formal analysis, Validation, Investigation, Writing - review and editing

    Competing interests

    No competing interests declared

15. Corinne Vigouroux

    1. Sorbonne Université-Inserm UMRS_938, Centre de Recherche Saint-Antoine (CRSA), Paris, France
    2. Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
    3. Centre National de Référence des Pathologies Rares de l’Insulino-Sécrétion et de l’Insulino-Sensibilité (PRISIS), Service de Diabétologie et Endocrinologie de la Reproduction, Hôpital Saint-Antoine, AP-HP, Paris, France
    4. Laboratoire commun de Biologie et Génétique Moléculaires, Hôpital Saint-Antoine, AP-HP, Paris, France

    Contribution

    Conceptualization, Formal analysis, Validation, Investigation, Writing - review and editing

    Competing interests

    No competing interests declared

16. Fabrizio Andreelli

    1. Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
    2. Service de Diabétologie-Métabolisme, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France
    3. Sorbonne Université-Inserm UMRS_1269, Paris, France

    Contribution

    Conceptualization, Formal analysis, Validation, Investigation, Writing - review and editing

    Competing interests

    No competing interests declared

17. Isabelle Jeru

    1. Sorbonne Université-Inserm UMRS_938, Centre de Recherche Saint-Antoine (CRSA), Paris, France
    2. Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
    3. Laboratoire commun de Biologie et Génétique Moléculaires, Hôpital Saint-Antoine, AP-HP, Paris, France

    Contribution

    Conceptualization, Data curation, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Methodology, Writing - original draft, Project administration, Writing - review and editing

    For correspondence

    isabelle.jeru@aphp.fr

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-7171-0577

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