A novel NKX2.1 mutation in a family with hypothyroidism and benign hereditary chorea.
BACKGROUND
We studied a boy with congenital hypothyroidism, benign hereditary chorea, and respiratory distress. His mother and his grandfather were affected by hypothyroidism with a late onset and benign hereditary chorea. The aim of this study was to establish the genetic defects that cause that phenotype and study the molecular mechanisms of the pathology.


METHODS
NKX2.1, PAX8, NKX2.5, and TAZ genes were sequenced.


RESULTS
Direct sequencing of the NKX2.1 gene showed, in all the affected, a new heterozygous mutation from cytosine to adenine in the second base of the triplet encoding for the amino acid at position 145. The mutation (C609A) is responsible for a change from serine to a stop codon (S145X). We also demonstrated that the mutant protein is predominantly in the cytoplasm and unable to translocate into the nucleus. Of note, the S145X mutation produces variable phenotypes in the affected members of the family. No mutations have been identified in the NKX2.5, PAX8, and TAZ genes.


CONCLUSIONS
Our study extends the knowledge of the functional effect of NKX2.1 mutations and further highlights the complexities of genotype-phenotype correlation in the NKX2.1 deficiency syndromes.
Ferrara
Alfonso Massimiliano
AM
Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Università degli Studi di Napoli Federico II, Napoli, Italy.
De Michele
Giuseppe
G
Salvatore
Elena
E
Di Maio
Luigi
L
Zampella
Emilia
E
Capuano
Serena
S
Del Prete
Giuseppina
G
Rossi
Giuseppina
G
Fenzi
Gianfranco
G
Filla
Alessandro
A
Macchia
Paolo Emidio
PE
D002819:Chorea / Q000235:genetics*; D005192:Family Health; D005260:Female; D006579:Heterozygote; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007037:Hypothyroidism / Q000235:genetics*; D008297:Male; D008957:Models, Genetic; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics; D012120:Respiration Disorders / Q000235:genetics; D017422:Sequence Analysis, DNA; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000235:genetics*
D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; D009687:Nuclear Proteins; D000072636:PAX8 Transcription Factor; C083325:PAX8 protein, human; D051761:Paired Box Transcription Factors; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors