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SPRED1 Germline Mutations Caused a Neurofibromatosis Type 1

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SPRED1 Germline Mutations Caused a Neurofibromatosis Type 1 SPRED1 germline mutations caused a neurofibromatosis type 1 overlapping phenotype Eric Pasmant, Audrey Sabbagh, Nadine Hanna, Julien Masliah-Planchon, Emilie Jolly, Philippe Goussard, Paola Ballerini, François Cartault, Sébastien Barbarot, Judith Landman-Parker, et al. To cite this version: Eric Pasmant, Audrey Sabbagh, Nadine Hanna, Julien Masliah-Planchon, Emilie Jolly, et al.. SPRED1 germline mutations caused a neurofibromatosis type 1 overlapping phenotype. Journal of Medical Genetics, BMJ Publishing Group, 2009, 46 (7), pp.425. 10.1136/jmg.2008.065243. hal-00552683 HAL Id: hal-00552683 https://hal.archives-ouvertes.fr/hal-00552683 Submitted on 6 Jan 2011 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. SPRED1 germline mutations caused a neurofibromatosis type 1 overlapping phenotype Eric Pasmant1,2, Audrey Sabbagh1,2, Nadine Hanna1,2, Julien Masliah-Planchon2, Emilie Jolly2, Philippe Goussard2, Paola Ballerini3, François Cartault4, Sébastien Barbarot5, Judith Landman-Parker6, Nadem Soufir7, Béatrice Parfait1,2, Michel Vidaud1,2, Pierre Wolkenstein8, Dominique Vidaud1,2: Réseau NF France 1UMR745 INSERM, Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, 4 av. de l’Observatoire, 75006, Paris, France; 2Service de Biochimie et de Génétique Moléculaire, Hôpital Beaujon, AP-HP, 100 Bd du Gal Leclerc, 92110, Clichy, France; 3Service d’Hématologie Biologique, Hôpital Armand Trousseau, AP-HP, 26 Av. du Dr Arnold-Netter, 75012, Paris, France; 4Service de Génétique, Centre hospitalier Félix Guyon, Bellepierre, 97405, Saint- Denis, France; 5Service de Dermatologie, Hôpital Hôtel Dieu, Place Alexis Ricordeau, 44093, Nantes, France; 6Service d’Oncologie Pédiatrique, Hôpital Armand Trousseau, AP-HP, 26 Av. du Dr Arnold-Nette, 75012, Paris, France; 7Service de Biochimie B Hormonale, Métabolique et Génétique, Hôpital Bichat Claude-Bernard, AP-HP, 46 rue Henri-Huchard, 75018 Paris, France 8Service de Dermatologie, Hôpital Henri Mondor-AP-HP, Université Paris 12, 51 av. du Mal de Lattre de Tassigny, 94000, Créteil, France 1 *Correspondence to Eric Pasmant, UMR745 INSERM, Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, 4 avenue de l’Observatoire, 75006, Paris, France (Phone: (33) 1 53 73 97 25; Fax: (33) 1 44 07 17 54; E-mail: [email protected]). KEY WORDS: SPRED1; neurofibromatosis type 1-like syndrome; Legius syndrome 2901 words 2 ABSTRACT: Objective: Germline loss-of-function mutations in the SPRED1 gene have recently been identified in patients fulfilling the National Institutes of Health (NIH) diagnostic criteria for neurofibromatosis type 1 (NF1) but with no NF1 (neurofibromin 1) mutation found, suggesting a neurofibromatosis type 1-like syndrome. Methods: 61 index cases with NF1 clinical diagnosis but no identifiable NF1 mutation were screened for SPRED1 mutation. Results: We described one known SPRED1 mutation (c.190C>T leading to p.Arg64Stop) and four novel mutations (c.637C>T leading to p.Gln213Stop, c.2T>C leading to p.Met1Thr, c.46C>T leading to p.Arg16Stop, and c.1048_1060del leading to p.Gly350fs) in five French families. Their NF1-like phenotype was characterized by a high prevalence of café-au-lait spots, freckling, learning disability, and an absence of neurofibromas and Lisch nodules in agreement with the original description. However, we did not observe Noonan-like dysmorphy. It is noteworthy that one patient with the p.Arg16Stop mutation developed a monoblastic acute leukaemia. Conclusions: In our series, SPRED1 mutations occurred with a prevalence of 0.5% in NF1 patients and in 5% of NF1 patients displaying a NF1-like phenotype. SPRED1 mutated patients did not display any specific dermatologic features that were not present in NF1 patients, except for the absence of neurofibromas that seem to be a specific clinical feature of NF1. The exact phenotypic spectrum and the putative complications of this NF1 overlapping syndrome, in particular haematological malignancies, remain to be further characterized. NIH diagnostic criteria for NF1 must be revised in view of this newly characterized Legius syndrome in order to establish a specific genetic counselling. 3 INTRODUCTION Germline mutations in genes involved in the Ras-mitogen activated protein kinase (MAPK) signalling pathway have been reported in several phenotypically overlapping syndromes with autosomal dominant transmission.[1] These observations provided a unifying mechanism -- Ras MAPK pathway constitutive activation -- leading to neuro- cardio-facial-cutaneous (NCFC) syndromes (Figure 1). These rare diseases include neurofibromatosis 1 (NF1, OMIM 162200), Noonan syndrome (NS, OMIM 163950), LEOPARD syndrome (LS, OMIM 151100), cardio-facio-cutaneous syndrome (CFC, OMIM 115150), and Costello syndrome (CS, OMIM 218040). Predisposition to malignancies is a known feature of NCFC syndromes with the exception of CFC.[2] NF1 has a birth incidence of ~1/3000 and has been showed to be caused by autosomal dominant loss of function mutations of the NF1 (neurofibromin 1; NM_000267) gene in approximately 95% of patients fulfilling the National Institutes of Health (NIH) clinical diagnostic criteria.[3,4,5] NF1 is located in 17q11.2 and contains 60 translated exons distributed over ~350 kb. Most of the NF1 mutations (90 to 95%) are intragenic mutations (point mutation, splice mutation, small deletion, insertion, or duplication). The remaining NF1 mutations (5 to 10%) are microdeletions encompassing the entire NF1 gene and its neighbouring genes.[6] The protein encoded by NF1 (neurofibromin) is a Ras-GTPase activating protein (Ras-GAP) that acts as a negative regulator of the Ras-MAPK cascade.[7] Germline dominant loss-of-function mutations in the SPRED1 (sprouty-related, EVH1 domain containing 1; NM_152594) gene have recently been identified in five unrelated families and seven additional patients fulfilling the NIH diagnostic criteria for NF1 although no NF1 mutation was found.[8] Remarkably, their phenotype referred as neurofibromatosis type 1-like syndrome (NFLS, OMIM 611431) consisted 4 of multiple café-au-lait spots, axillary freckling, and macrocephaly but without neurofibromas and Lisch nodules. The SPRED1 gene, located in 15q13.2, contains seven coding exons, and encodes the SPRED1 protein. Sprouty (SPRY1, -2, -3, and -4) and SPRED (SPRED1, -2, and -3) proteins are an evolutionarily conserved family of membrane-associated negative regulators of growth factor-induced ERK activation.[9,10] SPRED1 specifically inhibits MAPK signalling by suppressing Raf phosphorylation and activation.[11] In the present study, we confirmed the existence of loss-of-function mutations of SPRED1 and the characterization of a NCFC syndrome with a NF1 overlapping phenotype. We identified three nonsense mutations, one missense mutation, and one frameshift deletion of SPRED1 among 61 families fulfilling NIH diagnostic criteria for NF1 but with no identifiable NF1 mutation. We then developed a molecular diagnostic algorithm for individuals displaying a NF1-like phenotype tailored to routine clinical practice. PATIENTS, MATERIALS, AND METHODS Patients A database devoted to neurofibromatosis 1 has been established in France thanks to a grant from the French Clinical Research Program (coordinator: Pr. P. Wolkenstein, Henri Mondor Hospital, Créteil, France). The collection consists of 561 families, including 1697 individuals among which 1083 were NF1 patients fulfilling the NIH diagnostic criteria. The phenotype of each patient was described in a standardised way and was coupled with a comprehensive analysis of the NF1 mutational spectrum including intragenic microsatellites polymorphisms study, NF1 sequencing at both RNA and DNA levels, and real-time PCR-based gene dosage (data not shown). 5 Among the 561 NF1 index cases, a NF1 mutation was successfully identified in 512 individuals. The 49 NF1 index cases lacking NF1 mutations were selected as a first panel from this NF-France database to be screened for SPRED1 mutation. A second panel of 12 NF1 clinically diagnosed index cases with no NF1 mutation was phenotypically selected from routine genetic counselling: their phenotypes lied within the NF1 spectrum but were distinctive, with a high prevalence of café-au-lait spots, axillary, and groin freckling but absence of neurofibromas and Lisch nodules. All blood samples drawn for nucleic acids (DNAs and RNAs) extraction were collected after informed consent. DNA and RNA extraction High-molecular-weight DNA was prepared by standard proteinase K digestion followed by phenol-chloroform extraction from whole-blood leukocytes. Total RNA was extracted from whole-blood leukocytes by using the acid-phenol guanidium method. The quality of the nucleic acids was determined by electrophoresis through agarose gels and staining with ethidium bromide (DNA and RNA) and the 18S and 28S RNA bands were visualized under ultraviolet light (RNA). The somatic leukaemia DNA was extracted from bone marrow of patient II: 1 in Family 4 (showing 85% of blastic cells)
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