Sonic Hedgehog mutations are not a common cause of congenital hypopituitarism in the absence of complex midline cerebral defects

Paulo, Sabrina S; Fernandes-Rosa, Fábio Luiz; Turatti, Wendy; Coeli-Lacchini, Fernanda Borchers; Martinelli, Carlos Eduardo; Nakiri, Guilherme S.; Moreira, Ayrton Custódio; Santos, Antonio Cardoso dos; Castro, Margaret de; Antonini, Sonir Roberto Rauber

doi:10.1111/cen.12565

Cited by 12 publications

(13 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The exact frequency ofGLI2 mutations in patients with hypopituitarism is difficult to establish due to the large phenotypic variability of the studied cohorts. [17][18][19]21,24 Moreover, GLI2 is a large and highly In the present study, we report five unrelated subjects bearing five non-synonymous GLI2 variations in a cohort of 145 CPHD patients with or without extra-pituitary findings all at the heterozygous state. All the variants were absent in the public databases or if present, the frequency was not reported or extremely low (0.0001735) and predicted to be pathogenic by at least one prediction software ( The most striking results were observed for theGLI2ΔN-p.575H…”

Section: Discussionmentioning

confidence: 82%

“…The exact frequency of GLI2 mutations in patients with hypopituitarism is difficult to establish due to the large phenotypic variability of the studied cohorts . Moreover, GLI2 is a large and highly polymorphic gene with several rare variations reported in public databases making the establishment of the variants pathogenicity difficult without performing functional studies.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Novel GLI2 mutations identified in patients with Combined Pituitary Hormone Deficiency (CPHD): Evidence for a pathogenic effect by functional characterization

Babu

Fanelli

Mellone

et al. 2019

Clinical Endocrinology

View full text Add to dashboard Cite

Summary Context The Gli‐family of zinc‐finger transcription factors regulates the Sonic Hedgehog (Shh) signalling pathway that plays a key role in early pituitary and ventral forebrain development. Heterozygous GLI2 loss of function mutations in humans have been reported in holoprosencephaly (HPE), HPE‐like phenotypes associated with pituitary anomalies and combined pituitary hormone deficiency with or without other extra‐pituitary findings. Objective The aim of this study was the search for GLI2 mutations in a cohort of Italian CPHD patients and the assessment of a pathogenic role for the identified variants through in vitro studies. Patients One hundred forty‐five unrelated CPHD patients diagnosed with or without extra‐pituitary manifestations were recruited from different Italian centres. Methods The GLI2 mutation screening was carried out through direct sequencing of all the 13 exons and intron‐exon boundaries. Luciferase reporter assays were performed to evaluate the role of the detected missense variants. Results Five different novel heterozygous non‐synonymous GLI2 variants were identified in five patients. The mutations were three missense (p.Pro386Leu, p.Tyr575His, p.Ala593Val), one frameshift (p.Val1111Glyfs*19) and one nonsense (p.Arg1226X). The latter two mutants are likely pathogenic since they lead to a truncated protein. The in vitro functional study of the plasmids bearing two of the three missense variants (namely p.Tyr575His and p.Ala593Val) revealed a significant reduction in transcriptional activity. Conclusion In conclusion, the analysis of GLI2 in individuals with CPHD led to the identification of five variations with a likely negative impact on the GLI2 protein, confirming that GLI2 is an important causative gene in CPHD. The functional in vitro study analysis performed on the missense variations were useful to strengthen the hypothesis of pathogenicity.

show abstract

Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Novel GLI2 mutations identified in patients with Combined Pituitary Hormone Deficiency (CPHD): Evidence for a pathogenic effect by functional characterization

Babu

Fanelli

Mellone

et al. 2019

Clinical Endocrinology

View full text Add to dashboard Cite

show abstract

“…Among the six patients with hypopituitarism, four had IGHD and two had CPHD, independent of age. The two patients reported by Paulo et al (2015). had a median solitary maxillary incisor, one with cleft palate, but this was not observed in the patients studied by França et al (2010).…”

Section: Human Mutationsmentioning

confidence: 87%

“…The largest family with GLI2 mutations reported to date had the p.Leu788fsX794 mutation (França et al 2010, Paulo et al 2015. In the family reported by França et al (2010), the ten subjects who tested positive for the mutation also had polydactyly, whereas in the two distant relatives with the same mutation studied by Paulo et al (2015) in a different city, polydactyly was not observed. Among the six patients with hypopituitarism, four had IGHD and two had CPHD, independent of age.…”

Section: Human Mutationsmentioning

confidence: 96%

See 1 more Smart Citation

Role of GLI2 in hypopituitarism phenotype

Arnhold¹,

França²,

Carvalho³

et al. 2015

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

GLI2 is a zinc-finger transcription factor involved in the Sonic Hedgehog pathway. Gli2 mutant mice have hypoplastic anterior and absent posterior pituitary glands. We reviewed the literature for patients with hypopituitarism and alterations in GLI2. Twenty-five patients (16 families) had heterozygous truncating mutations, and the phenotype frequently included GH deficiency, a small anterior pituitary lobe and an ectopic/undescended posterior pituitary lobe on magnetic resonance imaging and postaxial polydactyly. The inheritance pattern was autosomal dominant with incomplete penetrance and variable expressivity. The mutation was frequently inherited from an asymptomatic parent. Eleven patients had heterozygous non-synonymous GLI2 variants that were classified as variants of unknown significance, because they were either absent from or had a frequency lower than 0.001 in the databases. In these patients, the posterior pituitary was also ectopic, but none had polydactyly. A third group of variants found in patients with hypopituitarism were considered benign because their frequency was R0.001 in the databases. GLI2 is a large and polymorphic gene, and sequencing may identify variants whose interpretation may be difficult. Incomplete penetrance implies in the participation of other genetic and/or environmental factors. An interaction between Gli2 mutations and prenatal ethanol exposure has been demonstrated in mice dysmorphology. In conclusion, a relatively high frequency of GLI2 mutations and variants were identified in patients with congenital GH deficiency without other brain defects, and most of these patients presented with combined pituitary hormone deficiency and an ectopic posterior pituitary lobe. Future studies may clarify the relative role and frequency of GLI2 alterations in the aetiology of hypopituitarism.

show abstract

Clinical and Biochemical Features of Hypopituitarism Among Brazilian Children With Zika Virus–Induced Microcephaly

et al. 2021

Self Cite

View full text Add to dashboard Cite

IMPORTANCE The Zika virus infects progenitor neuron cells, disrupts cerebral development, and, in mice, drives hypothalamic defects. Patients with microcephaly caused by congenital Zika infection present with midline cerebral defects, which may result in hypopituitarism. OBJECTIVE To analyze postnatal growth and the presence of clinical and biochemical features associated with hypopituitarism in children with congenital Zika infections. DESIGN, SETTING, AND PARTICIPANTS In this prospective cohort study at 2 public referral hospitals in Bahia, Brazil, specializing in the treatment of congenital Zika infection, clinical data and growth parameters of 65 patients with the infection were evaluated. Data were analyzed from April 2017 through July 2018. EXPOSURE Congenital Zika infection. MAIN OUTCOMES AND MEASURESLength, weight, and head circumference were measured at birth and during follow up (ie, at 27 months of life) for each patient. Basal levels of free thyroxine, thyrotropin, cortisol, corticotropin, prolactin, insulin-like growth factor 1, insulin-like growth factor binding protein 3, urine and plasma osmolality, electrolytes, glucose, and insulin were evaluated at the age of 26 months to 28 months. All patients underwent central nervous system computed tomography scans and ophthalmic and otoacoustic evaluations at the time of this investigation or had done so previously. RESULTSAmong 65 patients (38 [58.4%] male; median [interquartile range] age at enrollment, 27 [26-28] months), 61 patients presented with severe brain defects (93.8%), including corpus callosum agenesis or hypoplasia (ie, midline brain defects; 25 patients [38.5%]) and optic nerve atrophy (38 patients [58.5%]). Most patients presented with severe neurodevelopmental delay (62 of 64 patients [96.9%]). Past or present clinical signs of hypopituitarism were rare, occurring in 3 patients (4.6%). Severe microcephaly, compared with mild or moderate microcephaly, was associated with a shorter length by median (interquartile range) z score at birth

show abstract

Sonic Hedgehog mutations are not a common cause of congenital hypopituitarism in the absence of complex midline cerebral defects

Cited by 12 publications

References 42 publications

Novel GLI2 mutations identified in patients with Combined Pituitary Hormone Deficiency (CPHD): Evidence for a pathogenic effect by functional characterization

Novel GLI2 mutations identified in patients with Combined Pituitary Hormone Deficiency (CPHD): Evidence for a pathogenic effect by functional characterization

Role of GLI2 in hypopituitarism phenotype

Clinical and Biochemical Features of Hypopituitarism Among Brazilian Children With Zika Virus–Induced Microcephaly

Contact Info

Product

Resources

About