POU1F1 – Panhypopituitarism

POU1F1 encodes the pituitary-specific transcription factor Pit-1, which drives differentiation and hormone gene expression in somatotropes, lactotropes, and thyrotropes. Biallelic POU1F1 variants cause autosomal recessive panhypopituitarism, characterized by growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH) deficiencies, often with pituitary hypoplasia on MRI.

Genetic Evidence

Autosomal recessive inheritance is supported by multiple consanguineous families: four siblings homozygous for c.404T>G (p.Phe135Cys) (PMID:8768831), two siblings with c.499C>A (p.Gln167Lys) de novo (PMID:12904605), and additional homozygous or compound heterozygous variants in at least 20 unrelated probands (PMID:8768831, PMID:9485179). Segregation in eight affected relatives across consanguineous pedigrees and recurrence of founder alleles underscore robust genetic linkage.

Variant spectrum includes 12 missense changes within the POU-specific and homeo domains (e.g., p.Phe135Cys, p.Ser179Arg, p.Gln167Lys), six loss-of-function alleles (nonsense, frameshift, splice), and two intronic splice-site variants resulting in exon skipping (e.g., c.214+1G>T). Recurrent alleles such as p.Arg271Trp are noted in diverse populations.

Functional Evidence

In vitro transactivation assays demonstrate that Phe135Cys and Ser179Arg markedly reduce promoter activation of GH1, PRL, and TSHB without abolishing DNA binding (PMID:8768831, PMID:16968807). The P24L transactivation-domain mutant fails to recruit CREB-binding protein and lose cAMP responsiveness (PMID:12200420). These concordant mechanistic studies confirm impaired Pit-1 function as the pathogenic basis.

Clinical Features and Utility

Patients present in infancy with isolated GH deficiency, evolving PRL and TSH deficits, growth retardation, and central hypothyroidism (HP:0000821, HP:0000824, HP:0008202), often requiring multi-hormone replacement. MRI typically reveals anterior pituitary hypoplasia. Genetic diagnosis informs prognosis, guides hormone therapy, and avoids unnecessary testing for other etiologies.

Key Take-home: POU1F1 biallelic mutations cause definitive autosomal recessive panhypopituitarism; early molecular testing enables targeted hormone replacement and family counseling.

References

• The Journal of Clinical Endocrinology and Metabolism • 1996 • A new mutation of the gene encoding the transcription factor Pit-1 is responsible for combined pituitary hormone deficiency. PMID:8768831
• Hormone Research • 1998 • Central hypothyroidism reveals compound heterozygous mutations in the Pit-1 gene. PMID:9485179
• The Journal of Clinical Endocrinology and Metabolism • 2006 • Identification and functional analysis of the novel S179R POU1F1 mutation associated with combined pituitary hormone deficiency. PMID:16968807
• Pediatric Research • 2003 • The de novo Q167K mutation in the POU1F1 gene leads to combined pituitary hormone deficiency in an Italian patient. PMID:12904605
• The Journal of Biological Chemistry • 2002 • Novel function of the transactivation domain of a pituitary-specific transcription factor, Pit-1. PMID:12200420

Evidence Based Scoring (AI generated)