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Functional characterization of a heterozygous GLI2 missense mutation in patients with multiple pituitary hormone deficiency.

ABSTRACT: The GLI2 transcription factor is a major effector protein of the sonic hedgehog pathway and suggested to play a key role in pituitary development. Genomic GLI2 aberrations that mainly result in truncated proteins have been reported to cause holoprosencephaly or holoprosencephaly-like features, sometimes associated with hypopituitarism.Our objective was to determine the frequency of GLI2 mutations in patients with multiple pituitary hormone deficiency (MPHD).Patients were selected from participants in the Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS) program. Patients with mutations within established candidate genes were excluded.A total of 165 patients with MPHD defined as GH deficiency and at least 1 additional pituitary hormone deficiency were studied regardless of the presence of extrapituitary clinical manifestations.Prevalence of GLI2 variations in MPHD patients was assessed and detailed phenotypic characterization is given. Transcriptional activity of identified GLI2 variants was evaluated by functional reporter assays.In 5 subjects, 4 heterozygous missense variants were identified, of which 2 are unpublished so far. One variant, p.R516P, results in vitro in a complete loss of protein function. In addition to GH deficiency, the carrier of the mutation demonstrates deficiency of thyrotrope and gonadotrope function, a maldescended posterior pituitary lobe, and polydactyly, but no midline defects.For the first time, we show that heterozygous amino acid substitutions within GLI2 may lead to MPHD with mild extrapituitary findings. The phenotype of GLI2 mutations is variable, and penetrance is incomplete. GLI2 mutations are associated with anterior pituitary hypoplasia, and frequently, ectopy of the posterior lobe occurs.

SUBMITTER: Flemming GM

PROVIDER: S-EPMC3590478 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Functional characterization of a heterozygous GLI2 missense mutation in patients with multiple pituitary hormone deficiency.

Flemming G M C GM Klammt J J Ambler G G Bao Y Y Blum W F WF Cowell C C Donaghue K K Howard N N Kumar A A Sanchez J J Stobbe H H Pfäffle R W RW

The Journal of clinical endocrinology and metabolism 20130213 3

<h4>Context</h4>The GLI2 transcription factor is a major effector protein of the sonic hedgehog pathway and suggested to play a key role in pituitary development. Genomic GLI2 aberrations that mainly result in truncated proteins have been reported to cause holoprosencephaly or holoprosencephaly-like features, sometimes associated with hypopituitarism.<h4>Objective</h4>Our objective was to determine the frequency of GLI2 mutations in patients with multiple pituitary hormone deficiency (MPHD).<h4> ...[more]

PMID: 23408573

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Project description:BackgroundAsparagine synthetase deficiency (ASNSD) is a rare pediatric congenital disorder that clinically manifests into severe progressive microcephaly, global developmental delay, spastic quadriplegia, and refractory seizures. ASNSD is caused by inheritable autosomal recessive mutations in the asparagine synthetase (ASNS) gene.MethodsWe performed whole-exome sequencing using the patient's peripheral blood, and newly discovered mutations were subsequently verified in the patient's parents via Sanger sequencing. Software-based bioinformatics analyses (protein sequence conservation analysis, prediction of protein phosphorylation sites, protein structure modeling, and protein stability prediction) were performed to investigate and deduce their downstream effects.ResultsIn this article, we summarized all the previously reported cases of ASNSD and that of a Chinese girl who was clinically diagnosed with ASNSD, which was later confirmed via genetic testing. Whole-exome sequencing revealed two compound heterozygous missense mutations within the ASNS (c.368T > C, p.F123S and c.1649G > A, p.R550H). The origin of the two mutations was also verified in the patient's parents via Sanger sequencing. The mutation c.368T > C (p.F123S) was discovered and confirmed to be novel and previously unreported. Using software-based bioinformatics analyses, we deduced that the two mutation sites are highly conserved across a wide range of species, with the ability to alter different phosphorylation sites and destabilize the ASNS protein structure. The newly identified p.F123S mutation was predicted to be the most significantly destabilizing and detrimental mutation to the ASNS protein structure, compared to all other previously reported mutations.ConclusionEvidently, the presence of these compound heterozygous mutations could lead to severe clinical phenotypes and serve as a potential indicator for considerably higher risk with less optimistic prognosis in ASNSD patients.

Dataset Information

Functional characterization of a heterozygous GLI2 missense mutation in patients with multiple pituitary hormone deficiency.

Publications

Functional characterization of a heterozygous GLI2 missense mutation in patients with multiple pituitary hormone deficiency.

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