expression pédiatrique
  • Médecine

Laboratory of childhood genetic diseases

MRSU 933

  • Fédération

Our research unit (INSERM / Sorbonne University), in close connection with the molecular diagnostic activity of the hospital laboratory (AP-HP / Sorbonne University), is dedicated to the study of the physiopathology of three groups of human diseases with a genetic component: pulmonary diseases, auto-inflammatory diseases and developmental diseases. For all these diseases, cohorts of patients, exceptional both in size and phenotypic characterization, have been formed over the years. We combine genetic analyses and different molecular and cellular biology approaches to characterize the molecular and cellular bases of these diseases, which are still incompletely understood in the majority of these patients.

Single team research unit – 3 groups of rare diseases

Primary ciliary dyskinesia (PCD [MIM: 244400]) is a group of clinically and genetically heterogeneous disorders caused by dysfunction of motile cilia. In contrast to primary cilia, that protrude from the apical surface of most eukaryotic cells and acts as antennae sensing the external environment, motile cilia are only present at airway, ependymal and tubal epithelia, ensuring the transport of fluid; as well as in nodal cells to define the laterality of internal organs.

In PCD, the defect of motile cilia leads to impaired mucociliary clearance and early recurrent airway infections. About one person in 15,000 is concerned 1, and given the key role of motile cilia in the establishment of left-right asymmetry during embryogenesis 2, nearly 50% of those individuals display a situs inversus thereby defining the Kartagener syndrome. In addition, as the microtubule-based structure of motile cilia, the axoneme, is close to that of sperm flagella, most male individuals are also infertile. In most instances, PCD is transmitted as an autosomal recessive trait. Although rare, PCD is the most common ciliopathy.

The diagnosis of PCD is classically based on the identification of functional and structural abnormalities of cilia. Depending on the patients, cilia may carry various axonemal defects: one of the most frequent corresponds to the absence of the outer and/or the inner dynein arms (ODA, IDA) that are the motors responsible of ciliary movement. Other axonemal defects can affect the central complex or the radial spokes (axonemal disorganization), but in some cases, no ultrastructural abnormalities are detected. As predicted from the high complexity of ciliary structure and function, there is ample room for genetic heterogeneity in PCD. Fifty-one genes have been implicated so far (see Figure 1). Each of the several hundreds of proteins that constitute a cilium could potentially cause the disease.

Autoinflammatory diseases (AIDs) are rare, clinically and genetically heterogeneous diseases characterized by recurrent, self-limiting febrile episodes with systemic inflammation and involvement of serous membranes, synovial membranes and skin. The most serious complication is the risk of developing inflammatory amyloidosis, which can lead to end-stage renal disease. According to the pathophysiological pathways involved, AIDs are schematically divided into:

  • inflammasomopathies (involving multiprotein complexes called inflammasomes)
  • interferonopathies (associated with deregulation of type I interferon)
  • other innate immune system impairments leading to inflammation

From a therapeutic point of view, depending on the gene and signaling pathway involved, specific biotherapies can be proposed to patients with AID (e.g., IL1 inhibitors are effective in some inflammasomopathies and JAK1/2 inhibitors in some type I interferonopathies).

The best known mendelian forms of AID are:

  • Familial Mediterranean Fever (FMF), of autosomal recessive inheritance, linked to mutations in the MEFV gene (encoding pyrin)
  • Cryopyrinopathies due to heterozygous mutations in NLRP3
  • the autosomal dominant TRAPS (TNF-Receptor Associated Periodic Syndrome) syndrome related to mutations in TNFRSF1A,
  • the autosomal recessive hyper-IgD syndrome caused by mutations in MVK

To date, more than 50 genes (such as NOD2, NLRP12, NLRC4, LPIN2, PSTPIP1, IL1RN, IL36RN, IL10RA, IL10RB, CARD14, PSMB8, TMEM173, TNFAIP3, TNFRS11A, and OTULIN) encoding key components of the innate immune system are involved in the pathophysiology of AID, with germline and somatic mosaic mutations identified from blood sampling.

Our team is interested in identifying the molecular etiologies of AID and understanding the underlying pathophysiological mechanisms, an essential step to improve diagnosis and management of patients. In the laboratory, we are studying

  • the molecular aspect (panels of candidate ID genes, WES/WGS, whole exome/genome sequencing)
  • the functional aspect in order to specify the signaling networks involved.

Depending on the candidate genes identified and the data that may be available on their function, we carry out functional studies in-vitro and ex-vivo.

With this genetic and functional approach we have recently identified the p.Ala441Val missense variation in NLRP3 as a pathogenic recurrent mutational event in NLRP3-associated autoinflammatory disease. We have also shown that in late-onset chronic urticaria, the search for autoinflammatory markers and somatic mosaic NLRP3 mutations may have important diagnostic and therapeutic consequences2. Moreover, our identification of mosaic mutations affecting the same NLRP3 amino acid (Glu569) led us to perform a comprehensive review of somatic and germline NLRP3 variants where we show that there are “hot spots” for somatic mutation, with only a few variants found in both the germline and somatic state. We conclude that the phenotypic spectrum of NLRP3-AIDs appears to be related to the germinal/mosaic status and localization of the underlying mutations. Our work on inflammatory amyloidosis show that human monocytes and macrophages can express serum amyloid A genes, mainly SAA1 thus contributing to the local inflammatory microenvironment.

Intellectual disabilities (ID) are neurodevelopmental disorders characterized by impaired intellectual functioning affecting learning, reasoning, and problem-solving skills, as well as deficits in adaptive behavior, impairing social and practical daily skills. ID is usually associated with autism spectrum disorders. ID affects 2-3% of the population and is a clinically and genetically heterogeneous disease. The genes involved in ID are very diverse and participate in multiple cellular processes and embryonic development.

Our team is interested in diagnosing and understanding the molecular causes of syndromic IDs and in particular the following syndromes :Mowat-Wilson syndrome (MWS, MIM # 235730) is characterized by microcephaly, epilepsy, cerebral malformations of the agenesis of the corpus callosum, Hirschsprung’s disease (or congenital megacolon), cardiac and renal anomalies. MWS is caused by de novo monoallelic mutations in ZEB2 encoding an essential transcription factor during embryonic development. Most of the mutations identified in MWS are truncating mutations or deletions responsible for a haploinsufficiency of ZEB2. We have shown that some missense mutations located in the C-terminal zinc finger domain of ZEB2 are responsible for a milder disease phenotype.

Goldberg-Shprintzen syndrome (GOSHS, MIM # 609460) combines severe ID, microcephaly, brain and heart abnormalities, and Hirschsprung’s disease. GOSHS is caused by biallelic mutations in KIAA1279 aka KIFBP (KIF1-binding protein) encoding a cytoplasmic protein that interacts with the cytoskeleton.

Pitt-Hopkins syndrome (PTHS, MIM # 610954) is characterized by severe ID, behavioral problems, and hyperventilation. PTHS is due to de novo monoallelic mutations in TCF4 encoding a transcription factor of the E-protein family. We described the diagnostic criteria for typical PTHS, showed that it is important to evoke this diagnosis in some cases of moderate ID , and contributed to recommendations for the management of this disease.

The CSDE1 gene (Cold Shock Domain-containing E1-alias UNR: Upstream of NRAS, MIM # 191510) has been implicated more recently in ID associated with autistic disorders. CSDE1 encodes a protein that regulates translation and mRNA stability and has been implicated in many biological processes such as cell migration and cycle, apoptosis, embryonic development, neurogenesis and neuronal differentiation. By studying a patient with a monoallelic mutation of CSDE1 responsible for haploinsufficiency, we clarified the clinical phenotype of this condition and showed the role of this factor in the Wnt/β-catenin pathway and in cell adhesion.


  • Irina GIURGEA

Tutelle hébergeante

  • Institut National de la Santé et de la Recherche Médicale | INSERM

Autres tutelles

  • Sorbonne Université


Adresse physique

Hôpital Trousseau, bât. Ketty Schwartz, 26, avenue Arnold Netter
75571 Paris Cedex 12

Adresse postale

Hôpital Trousseau UF de Génétique clinique et moléculaire 26, avenue Arnold Netter
75571 Paris Cedex 12
26 Avenue du Dr Arnold Netter
26 Avenue du Dr Arnold Netter