Germline gain-of-function mutations of ALK disrupt central nervous system development

• Published in: Human mutation Vol. 32; no. 3; pp. 272 - 276
• Main Authors: de Pontual, Loïc, Kettaneh, Dania, Gordon, Christopher T, Oufadem, Myriam, Boddaert, Nathalie, Lees, Melissa, Balu, Laurent, Lachassinne, Eric, Petros, Andy, Mollet, Julie, Wilson, Louise C, Munnich, Arnold, Brugière, Laurence, Delattre, Olivier, Vekemans, Michel, Etchevers, Heather, Lyonnet, Stanislas, Janoueix-Lerosey, Isabelle, Amiel, Jeanne
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.03.2011; Hindawi Limited; Wiley
• Subjects: Adult; ALK; ALK protein; Brain; Brain stem; Brain Stem - abnormalities; Central nervous system; Central Nervous System - embryology; Embryogenesis; Encephalopathy; Female; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Infant; Infant, Newborn; Lymphoma; Magnetic resonance imaging; Mutation, Missense; Neuroblastoma; Neuroblastoma - congenital; Neuroblastoma - genetics; Neuroblastoma - pathology; neurodevelopment; Oncogenes; Protein-tyrosine kinase receptors; Receptor Protein-Tyrosine Kinases - genetics; Sympathetic ganglia; Syndrome; syndrome with cancer; Tumors; Life Sciences
• ISSN: 1059-7794; 1098-1004; 1098-1004
• DOI: 10.1002/humu.21442

Neuroblastoma (NB) is a frequent embryonal tumor 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) 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 harboring 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. Hum Mutat 32:277-281, 2011.