GERMLINE GAIN-OF-FUNCTION MUTATIONS of ALK DISRUPT CENTRAL NERVOUS SYSTEM DEVELOPMENT

Loic de Pontual (1) , Dania Kettaneh (2) , Chris Gordon (2) , Myriam Oufadem (2) , Nathalie Boddaert (2) , Melissa Less (3) , Laurent Balu (4) , Eric Lachassinne (5) , Andy Petros (3) , Julie Mollet (2) , Lc Wilson (3) , Arnold Munnich (2) , Laurence Brugière (6) , Olivier Delattre (7) , Michel Vekemans (2) , Heather C Etchevers (2) , Stanislas Lyonnet (2, 8, 9) , Isabelle Janouex Larosey (7) , Jeanne Amiel (2)

1 Service de Pédiatrie [Jean Verdier]
2 Inserm U781 - Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement
3 clinical genetic
4 reanimation pédiatrique
5 Hopital JeanVerdier
6 service d'oncologie pédiatrique
7 Institut Curie [Paris]
8 Service de Génétique Médicale [CHU Necker]
9 UPD5 - Université Paris Descartes - Paris 5

Neuroblastoma (NB) is a frequent embryonal tumour of sympathetic ganglia and adrenals with extremely variable outcome. Recently, somatic amplification and gain-of-function mutations of the anaplastic lymphoma receptor tyrosine kinase (ALK, MIM 105590) gene, either somatic or germline, were identified in a significant proportion of NB cases. Here we report a novel syndromic presentation associating congenital NB with severe encephalopathy and abnormal shape of the brainstem on brain MRI in two unrelated sporadic cases harbouring de novo, germline, heterozygous ALK gene mutations. Both mutations are gain-of-function mutations that have been reported in NB and NB cell lines. These observations further illustrate the role of oncogenes in both tumour predisposition and normal development, and shed light on the pleiotropic and activity-dependent role of ALK in humans. More generally, missing germline mutations relative to the spectrum of somatic mutations reported for a given oncogene may be a reflection of severe effects during embryonic development, and may prompt mutation screening in patients with extreme phenotypes.

Mots clés: Life Sciences

Loic de Pontual, Dania Kettaneh, Chris Gordon, Myriam Oufadem, Nathalie Boddaert, et al.. GERMLINE GAIN-OF-FUNCTION MUTATIONS of ALK DISRUPT CENTRAL NERVOUS SYSTEM DEVELOPMENT. Human Mutation, 2011, 32 (3), pp.272. ⟨10.1002/humu.21442⟩. ⟨hal-00616287⟩