POU1F1 Mutations in Combined Pituitary Hormone Deficiency: Differing Spectrum of Mutations in a Western-Indian Cohort and Systematic Analysis of World Literature

Overview

Journal Pituitary

Specialty Endocrinology

Date 2021 Mar 20

PMID 33742319

Citations 5

Authors

Swati Jadhav

Chakra Diwaker

Anurag R Lila

Jugal V Gada

Shantanu Kale

Vijaya Sarathi

Puja M Thadani

Sneha Arya

Virendra A Patil

Nalini S Shah

Tushar R Bandgar

Affiliations

Soon will be listed here.

Abstract

Context: POU1F1 mutations are prevalent in Indian CPHD cohorts. Genotype-phenotype correlation is not well-studied.

Aim: To describe phenotypic and genotypic spectrum of POU1F1 mutations in our CPHD cohort and present systematic review as well as genotype-phenotype analysis of all mutation-positive cases reported in world literature.

Methods: Retrospective study of POU1F1 mutation-positive patients from a western-Indian center. PRISMA guidelines based pubmed search of published literature of all mutation-positive patients.

Results: Our cohort had 15 POU1F1 mutation-positive patients (9 index, 6 relatives). All had severe GH, TSH and prolactin deficiencies (GHD, TSHD and PD). TSHD was diagnosed earliest followed by GHD (median ages: TSHD-6 months, GHD-3 years), while PD was more variable. Two sisters had central precocious puberty at 7 years of age. Pubic hair was deficient in all post-pubertal patients (females: P1-P2, males: P3-P4). Splice-site/intronic/frameshift mutations were most common, while missense/nonsense mutations were less frequent (33%). Review of world literature yielded 114 patients (82 index patients) from 58 studies. GHD was present in all patients. TSHD was spared in 12.5% and PD in 4.4% patients. Missense/nonsense mutations accounted for 75% of spectrum. Phenotype-genotype analysis revealed higher mean peak-GH levels (1.1 vs 0.2 ng/ml, p = 0.008) and lower prevalence of anterior-pituitary hypoplasia (63.6% vs 86.3%, p = 0.03) in patients with heterozygous than homozygous and compound heterozygous mutations.

Conclusions: We present largest series of POU1F1 mutation-positive patients. Precocious puberty and defective pubarche are lesser-appreciated phenotypic features. Our mutation spectrum is different from that of world literature. Patients with heterozygous mutations have milder phenotype.

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References

Fang Q, George A, Brinkmeier M, Mortensen A, Gergics P, Cheung L . Genetics of Combined Pituitary Hormone Deficiency: Roadmap into the Genome Era. Endocr Rev. 2016; 37(6):636-675. PMC: 5155665. DOI: 10.1210/er.2016-1101. View

Snell G . DWARF, A NEW MENDELIAN RECESSIVE CHARACTER OF THE HOUSE MOUSE. Proc Natl Acad Sci U S A. 1929; 15(9):733-4. PMC: 522547. DOI: 10.1073/pnas.15.9.733. View

Nagai K, Oubridge C, Jessen T, Li J, Evans P . Crystal structure of the RNA-binding domain of the U1 small nuclear ribonucleoprotein A. Nature. 1990; 348(6301):515-20. DOI: 10.1038/348515a0. View

Tatsumi K, Miyai K, Notomi T, Kaibe K, Amino N, Mizuno Y . Cretinism with combined hormone deficiency caused by a mutation in the PIT1 gene. Nat Genet. 1992; 1(1):56-8. DOI: 10.1038/ng0492-56. View

Pfaffle R, Blankenstein O, Wuller S, Kentrup H . Combined pituitary hormone deficiency: role of Pit-1 and Prop-1. Acta Paediatr Suppl. 2000; 88(433):33-41. DOI: 10.1111/j.1651-2227.1999.tb14401.x. View

Kale S, Gada J, Jadhav S, Lila A, Sarathi V, Budyal S . Genetic spectrum and predictors of mutations in four known genes in Asian Indian patients with growth hormone deficiency and orthotopic posterior pituitary: an emphasis on regional genetic diversity. Pituitary. 2020; 23(6):701-715. DOI: 10.1007/s11102-020-01078-4. View

de Zegher F, Pernasetti F, Vanhole C, Devlieger H, Van den Berghe G, Martial J . The prenatal role of thyroid hormone evidenced by fetomaternal Pit-1 deficiency. J Clin Endocrinol Metab. 1995; 80(11):3127-30. DOI: 10.1210/jcem.80.11.7593413. View

Gat-Yablonski G, Frumkin-Ben David R, Bar M, Potievsky O, Phillip M, Lazar L . Homozygous microdeletion of the POU1F1, CHMP2B, and VGLL3 genes in chromosome 3--a novel syndrome. Am J Med Genet A. 2011; 155A(9):2242-6. DOI: 10.1002/ajmg.a.34136. View

Shamseldin H, Maddirevula S, Nabil A, Al-Fadhil S, Al Tala S, Alkuraya F . Joint laxity in homozygotes for severe POU1F1 mutations. Am J Med Genet A. 2016; 170(12):3356-3358. DOI: 10.1002/ajmg.a.37941. View

10.

Aykut A, Onay H, Kose M, Erbas Canda E, Karaca E, Coker M . Two novel mutations in acid α-glucosidase gene in two patients with Pompe disease. J Pediatr Endocrinol Metab. 2014; 27(11-12):1265-7. DOI: 10.1515/jpem-2014-0107. View

11.

Bano G, Mansour S, Brice G, Ostergaard P, Mortimer P, Jeffery S . Pit-1 mutation and lipoedema in a family. Exp Clin Endocrinol Diabetes. 2009; 118(6):377-80. DOI: 10.1055/s-0029-1224154. View

12.

Birla S, Khadgawat R, Jyotsna V, Jain V, Garg M, Bhalla A . Identification of Novel PROP1 and POU1F1 Mutations in Patients with Combined Pituitary Hormone Deficiency. Horm Metab Res. 2016; 48(12):822-827. DOI: 10.1055/s-0042-117112. View

13.

Turton J, Reynaud R, Mehta A, Torpiano J, Saveanu A, Woods K . Novel mutations within the POU1F1 gene associated with variable combined pituitary hormone deficiency. J Clin Endocrinol Metab. 2005; 90(8):4762-70. DOI: 10.1210/jc.2005-0570. View

14.

Gat-Yablonski G, Lazar L, Pertzelan A, Phillip M . A novel mutation in PIT-1: phenotypic variability in familial combined pituitary hormone deficiencies. J Pediatr Endocrinol Metab. 2002; 15(3):325-30. DOI: 10.1515/jpem.2002.15.3.325. View

15.

Pernasetti F, Milner R, al Ashwal A, de Zegher F, Chavez V, Muller M . Pro239Ser: a novel recessive mutation of the Pit-1 gene in seven Middle Eastern children with growth hormone, prolactin, and thyrotropin deficiency. J Clin Endocrinol Metab. 1998; 83(6):2079-83. DOI: 10.1210/jcem.83.6.4901. View

16.

Sobrier M, Tsai Y, Perez C, Leheup B, Bouceba T, Duquesnoy P . Functional characterization of a human POU1F1 mutation associated with isolated growth hormone deficiency: a novel etiology for IGHD. Hum Mol Genet. 2015; 25(3):472-83. PMC: 5007599. DOI: 10.1093/hmg/ddv486. View

17.

Pfaffle R, DiMattia G, Parks J, Brown M, Wit J, Jansen M . Mutation of the POU-specific domain of Pit-1 and hypopituitarism without pituitary hypoplasia. Science. 1992; 257(5073):1118-21. DOI: 10.1126/science.257.5073.1118. View

18.

Morange-Ramos I, Barlier A, Gunz G, Figarella-Branger D, Cortet-Rudelli C, Grisoli F . Pit-1 gene expression in human lactotroph and somatotroph pituitary adenomas is correlated to D2 receptor gene expression. J Clin Endocrinol Metab. 1996; 81(9):3390-6. DOI: 10.1210/jcem.81.9.8784102. View

19.

Salemi S, Besson A, Eble A, Gallati S, Pfaffle R, Mullis P . New N-terminal located mutation (Q4ter) within the POU1F1-gene (PIT-1) causes recessive combined pituitary hormone deficiency and variable phenotype. Growth Horm IGF Res. 2003; 13(5):264-8. DOI: 10.1016/s1096-6374(03)00015-7. View

20.

Dasen J, OConnell S, FLYNN S, Treier M, Gleiberman A, Szeto D . Reciprocal interactions of Pit1 and GATA2 mediate signaling gradient-induced determination of pituitary cell types. Cell. 1999; 97(5):587-98. DOI: 10.1016/s0092-8674(00)80770-9. View