Tiziana de Filippis1, Federica Marelli1, Maria Cristina Vigone2, Marianna Di Frenna2, Giovanna Weber2, Luca Persani3. 1. Laboratory of Endocrine and Metabolic Research, IRCCS Istituto Auxologico Italiano, Milan, Italy ; Division of Endocrinology and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy. 2. Department of Pediatrics, Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy. 3. Laboratory of Endocrine and Metabolic Research, IRCCS Istituto Auxologico Italiano, Milan, Italy ; Division of Endocrinology and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy ; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
Abstract
OBJECTIVES: To verify the involvement of NKX2-1 gene in infants with brain-lung-thyroid (BLT) syndrome and hypothyroid phenotypes variable among congenital hypothyroidism (CH) or idiopathic mild hypothyroidism (IMH) of postnatal onset. METHODS: The candidates were selected by a case-finding approach in 130 CH and 53 IMH infants. The NKX2-1 gene was analyzed by direct sequencing and multiplex ligation-dependent probe amplification. The variants were studied in vitro, by expression analyses and luciferase bioassay. RESULTS: Four cases (3 CH and 1 IMH) consistent with BLT syndrome were identified. Two children were affected with respiratory distress and CH, but wild-type NKX2-1 gene. The remaining two presented choreic movements and no pulmonary involvement, but discrepant thyroid phenotypes: one had severe CH with lingual ectopy and the other one IMH with gland in situ. They were carriers of new de novo heterozygous frameshift mutations of NKX2-1 (c.177delG and c.153_166del14). The c.177delG leads to a prematurely truncated protein (p.H60TfsX11) with undetectable activity in vitro. The c.153_166del14 leads to the generation of an elongated aberrant protein (p.A52RfsX351) able to translocate into the nucleus, but completely inactive on a responsive promoter. CONCLUSIONS: Two novel heterozygous frameshift mutations of NKX2-1 were identified in 2 cases selected on the basis of a BLT-like phenotype among 183 hypothyroid infants. The atypical hypothyroid phenotypes of these 2 children (CH with lingual ectopy or IMH of postnatal onset) further expand the clinical spectrum that can be associated with NKX2-1 mutations.
OBJECTIVES: To verify the involvement of NKX2-1 gene in infants with brain-lung-thyroid (BLT) syndrome and hypothyroid phenotypes variable among congenital hypothyroidism (CH) or idiopathic mild hypothyroidism (IMH) of postnatal onset. METHODS: The candidates were selected by a case-finding approach in 130 CH and 53 IMH infants. The NKX2-1 gene was analyzed by direct sequencing and multiplex ligation-dependent probe amplification. The variants were studied in vitro, by expression analyses and luciferase bioassay. RESULTS: Four cases (3 CH and 1 IMH) consistent with BLT syndrome were identified. Two children were affected with respiratory distress and CH, but wild-type NKX2-1 gene. The remaining two presented choreic movements and no pulmonary involvement, but discrepant thyroid phenotypes: one had severe CH with lingual ectopy and the other one IMH with gland in situ. They were carriers of new de novo heterozygous frameshift mutations of NKX2-1 (c.177delG and c.153_166del14). The c.177delG leads to a prematurely truncated protein (p.H60TfsX11) with undetectable activity in vitro. The c.153_166del14 leads to the generation of an elongated aberrant protein (p.A52RfsX351) able to translocate into the nucleus, but completely inactive on a responsive promoter. CONCLUSIONS: Two novel heterozygous frameshift mutations of NKX2-1 were identified in 2 cases selected on the basis of a BLT-like phenotype among 183 hypothyroidinfants. The atypical hypothyroid phenotypes of these 2 children (CH with lingual ectopy or IMH of postnatal onset) further expand the clinical spectrum that can be associated with NKX2-1 mutations.
Authors: Joachim Pohlenz; Alexandra Dumitrescu; Dorothee Zundel; Ursula Martiné; Winfried Schönberger; Eugene Koo; Roy E Weiss; Ronald N Cohen; Shioko Kimura; Samuel Refetoff Journal: J Clin Invest Date: 2002-02 Impact factor: 14.808
Authors: Guido J Breedveld; Jeroen W F van Dongen; Cesare Danesino; Andrea Guala; Alan K Percy; Leon S Dure; Peter Harper; Lazarus P Lazarou; Herma van der Linde; Marijke Joosse; Annette Grüters; Marcy E MacDonald; Bert B A de Vries; Willem Frans M Arts; Ben A Oostra; Heiko Krude; Peter Heutink Journal: Hum Mol Genet Date: 2002-04-15 Impact factor: 6.150