STR mutations on chromosome 15q cause thyrotropin resistance by activating a primate-specific enhancer of MIR7-2/MIR1179.
Nat Genet
; 56(5): 877-888, 2024 May.
Article
en En
| MEDLINE
| ID: mdl-38714869
ABSTRACT
Thyrotropin (TSH) is the master regulator of thyroid gland growth and function. Resistance to TSH (RTSH) describes conditions with reduced sensitivity to TSH. Dominantly inherited RTSH has been linked to a locus on chromosome 15q, but its genetic basis has remained elusive. Here we show that non-coding mutations in a (TTTG)4 short tandem repeat (STR) underlie dominantly inherited RTSH in all 82 affected participants from 12 unrelated families. The STR is contained in a primate-specific Alu retrotransposon with thyroid-specific cis-regulatory chromatin features. Fiber-seq and RNA-seq studies revealed that the mutant STR activates a thyroid-specific enhancer cluster, leading to haplotype-specific upregulation of the bicistronic MIR7-2/MIR1179 locus 35 kb downstream and overexpression of its microRNA products in the participants' thyrocytes. An imbalance in signaling pathways targeted by these micro-RNAs provides a working model for this cause of RTSH. This finding broadens our current knowledge of genetic defects altering pituitary-thyroid feedback regulation.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Cromosomas Humanos Par 15
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Tirotropina
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Elementos de Facilitación Genéticos
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Repeticiones de Microsatélite
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MicroARNs
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Mutación
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Nat Genet
Asunto de la revista:
GENETICA MEDICA
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos