Pituitary Transcription Factor Mutations Leading to Hypopituitarism

Gergics, Péter

doi:10.1007/978-3-030-25905-1_13

Cited by 4 publications

(6 citation statements)

References 226 publications

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“…Hypothesized scenario of co‐contributing genetic effects modulating the penetrance of NR5A1 pathogenic variants. (A) Simplified schematic representation of a critical transcription factor cascade in the anterior pituitary development in humans (Refs 46,47…”

Section: Resultsmentioning

confidence: 99%

NR5A1 c.991‐1G > C splice‐site variant causes familial 46,XY partial gonadal dysgenesis with incomplete penetrance

Laan

Kasak

Timinskas

et al. 2020

Clinical Endocrinology

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Objective The study aimed to identify the genetic basis of partial gonadal dysgenesis (PGD) in a non‐consanguineous family from Estonia. Patients Cousins P (proband) 1 (12 years; 46,XY) and P2 (18 years; 46,XY) presented bilateral cryptorchidism, severe penoscrotal hypospadias, low bitesticular volume and azoospermia in P2. Their distant relative, P3 (30 years; 46,XY), presented bilateral cryptorchidism and cryptozoospermia. Design Exome sequencing was targeted to P1‐P3 and five unaffected family members. Results P1‐P2 were identified as heterozygous carriers of NR5A1 c.991‐1G > C. NR5A1 encodes the steroidogenic factor‐1 essential in gonadal development and specifically expressed in adrenal, spleen, pituitary and testes. Together with a previous PGD case from Belgium (Robevska et al 2018), c.991‐1G > C represents the first recurrent NR5A1 splice‐site mutation identified in patients. The majority of previous reports on NR5A1 mutation carriers have not included phenotype‐genotype data of the family members. Segregation analysis across three generations showed incomplete penetrance (<50%) and phenotypic variability among the carriers of NR5A1 c.991‐1G > C. The variant pathogenicity was possibly modulated by rare heterozygous variants inherited from the other parent, OTX2 p.P134R (P1) or PROP1 c.301_302delAG (P2). For P3, the pedigree structure supported a distinct genetic cause. He carries a previously undescribed likely pathogenic variant SOS1 p.Y136H. SOS1, critical in Ras/MAPK signalling and foetal development, is a strong novel candidate gene for cryptorchidism. Conclusions Detailed genetic profiling facilitates counselling and clinical management of the probands, and supports unaffected mutation carriers in the family for their reproductive decision making.

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Section: Resultsmentioning

confidence: 99%

NR5A1 c.991‐1G > C splice‐site variant causes familial 46,XY partial gonadal dysgenesis with incomplete penetrance

Laan

Kasak

Timinskas

et al. 2020

Clinical Endocrinology

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“…However, there are precedents for variable clinical features and incomplete penetrance with other cases of hypopituitarism. 18 Approximately 50% of IGHD progresses to CPHD, and this can even occur when the mutated gene is only expressed in GH-producing cells, i.e., GH1. 51 Even individuals with the same POU1F1 mutation (i.e., p.Glu230Lys) can present with either IGHD or CPHD, 52 indicating a contributing role for genetic background, epigenetic, and/or environmental factors.…”

Section: Discussionmentioning

confidence: 99%

“…14 Although alternative splicing of POU1F1 is evolutionarily conserved among vertebrates, the functional significance of the minor, beta isoform remains unclear. 10 The first case of a recessive POU1F1 loss of function was described in a child with combined pituitary hormone deficiency (CPHD [MIM: 613038, 262600, 221750, 262 700, 601538, 173110, 615849, 600577, 182230, 612079, and 602146]) born to consanguineous parents; 16 since then, many unique variants in POU1F1 have been reported in people with CPHD or isolated growth hormone deficiency (IGHD [MIM: 307200, 262400, 173100, 612781, 139250, 618157, 139191, 262500, 615925, and 618 160) [17][18][19][20][21][22][23] (reviewed in Jadhav et al 24 ). A few dominantnegative mutations have been reported that most likely act by interfering with the function of POU1F1 dimers.…”

Section: Introductionmentioning

confidence: 99%

High-throughput splicing assays identify missense and silent splice-disruptive POU1F1 variants underlying pituitary hormone deficiency

Gergics

Smith

Bando

et al. 2021

The American Journal of Human Genetics

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“…The reason for this variability in presentation is unknown. However, there are precedents for variable clinical features and incomplete penetrance with other cases of hypopituitarism 18 . Approximately 50% of IGHD progresses to CPHD, and this can even occur when the mutated gene is only expressed in GH-producing cells, i.e.…”

Section: Discussionmentioning

confidence: 99%

“…The first case of a recessive POU1F1 loss of function was described in a patient with CPHD born to consanguineous parents 16 , and since then thirty-seven unique variants in POU1F1 have been reported in patients with CPHD or IGHD [17][18][19][20][21][22][23] . A few dominant negative mutations have been reported: p.P76L alters the transactivation domain and causes completely penetrant IGHD 24 , p.K216E interferes with the ability of POU1F1 to interact with retinoic acid All rights reserved.…”

Section: Introductionmentioning

confidence: 99%

High-throughput splicing assays identify missense and silent splice-disruptivePOU1F1variants underlying pituitary hormone deficiency

Gergics

Smith

Bando

et al. 2021

Preprint

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Pituitary hormone deficiency occurs in ~1:4,000 live births. Approximately 3% of the cases are due to mutations in the alpha isoform of POU1F1, a pituitary-specific transcriptional activator. We found four separate heterozygous missense variants in unrelated hypopituitarism patients that were predicted to affect a minor isoform, POU1F1 beta, which can act as a transcriptional repressor. These variants retain repressor activity, but they shift splicing to favor the expression of the beta isoform, resulting in dominant negative loss of function. Using a high throughput splicing reporter assay, we tested 1,080 single nucleotide variants in POU1F1. We identified 113 splice disruptive variants, including 23 synonymous variants. We evaluated separate cohorts of hypopituitarism patients and found two different synonymous splice disruptive variants that co-segregate with hypopituitarism. This study underlines the importance of evaluating the impact of variants on splicing and provides a catalog for interpretation of variants of unknown significance in the POU1F1 gene.

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Pituitary Transcription Factor Mutations Leading to Hypopituitarism

Cited by 4 publications

References 226 publications

NR5A1 c.991‐1G > C splice‐site variant causes familial 46,XY partial gonadal dysgenesis with incomplete penetrance

NR5A1 c.991‐1G > C splice‐site variant causes familial 46,XY partial gonadal dysgenesis with incomplete penetrance

High-throughput splicing assays identify missense and silent splice-disruptive POU1F1 variants underlying pituitary hormone deficiency

High-throughput splicing assays identify missense and silent splice-disruptivePOU1F1variants underlying pituitary hormone deficiency

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