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Germline gain‐of‐function mutations of ALK disrupt central nervous system development
Author(s) -
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,
JanoueixLerosey Isabelle,
Amiel Jeanne
Publication year - 2011
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21442
Subject(s) - biology , germline , anaplastic lymphoma kinase , germline mutation , somatic cell , mutation , genetics , neuroblastoma , cancer research , phenotype , gene , medicine , lung cancer , cell culture , malignant pleural effusion
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. © 2011 Wiley‐Liss, Inc.