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. 2023 Mar 7:14:1066182.
doi: 10.3389/fendo.2023.1066182. eCollection 2023.

A GHRHR founder mutation causes isolated growth hormone deficiency type IV in a consanguineous Pakistani family

Safeer Ahmad  1 , Muhammad Zeeshan Ali  1 , Sumra Wajid Abbasi  2 , Safdar Abbas  1 , Iftikhar Ahmed  1 , Shakil Abbas  1 , Shoaib Nawaz  3 , Mubarak Ziab  4 , Ikhlak Ahmed  4 , Khalid A Fakhro  3   5   6 , Muzammil Ahmad Khan  1 , Ammira Al-Shabeeb Akil  3   4
Affiliations

A GHRHR founder mutation causes isolated growth hormone deficiency type IV in a consanguineous Pakistani family

Safeer Ahmad et al. Front Endocrinol (Lausanne). .

Abstract

Background: Isolated growth hormone deficiency (IGHD) is caused by a severe shortage or absence of growth hormone (GH), which results in aberrant growth and development. Patients with IGHD type IV (IGHD4) have a short stature, reduced serum GH levels, and delayed bone age.

Objectives: To identify the causative mutation of IGHD in a consanguineous family comprising four affected patients with IGHD4 (MIM#618157) and explore its functional impact in silico.

Methods: Clinical and radiological studies were performed to determine the phenotypic spectrum and hormonal profile of the disease, while whole-exome sequencing (WES) and Sanger sequencing were performed to identify the disease-causing mutation. In-silico studies involved protein structural modeling and docking, and molecular dynamic simulation analyses using computational tools. Finally, data from the Qatar Genome Program (QGP) were screened for the presence of the founder variant in the Qatari population.

Results: All affected individuals presented with a short stature without gross skeletal anomalies and significantly reduced serum GH levels. Genetic mapping revealed a homozygous nonsense mutation [NM_000823:c.G214T:p.(Glu72*)] in the third exon of the growth-hormone-releasing hormone receptor gene GHRHR (MIM#139191) that was segregated in all patients. The substituted amber codon (UAG) seems to truncate the protein by deleting the C-terminus GPCR domain, thus markedly disturbing the GHRHR receptor and its interaction with the growth hormone-releasing hormone.

Conclusion: These data support that a p.Glu72* founder mutation in GHRHR perturbs growth hormone signaling and causes IGHD type IV. In-silico and biochemical analyses support the pathogenic effect of this nonsense mutation, while our comprehensive phenotype and hormonal profiling has established the genotype-phenotype correlation. Based on the current study, early detection of GHRHR may help in better therapeutic intervention.

Keywords: GHRHR; Pakistani family; docking and simulation; isolated growth hormone deficiency (IGHD4); modeling; whole-exome sequencing.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Genealogical analysis and clinical description of patients. (A) Photographs of normal (V-5) and affected individuals (V-4, V-10, V-11, V-12). (B) Genotype integrated family genealogy. (C) Radiographs of the hands and feet of affected patients. (D) Sequence chromatograms of affected patients (V-4 and V-10) and normal individuals, including the parents (III-1 and IV-1).
Figure 2
Figure 2
Membrane topology of GHRHR: images of the transmembrane topology of the GHRHR protein.
Figure 3
Figure 3
3D structure and docking properties of GHRHR: (A–C) Normal and mutant models of the GHRHR protein and their superimposed images. (D, E) Normal and mutant GHRHR proteins docked with a close interactor (GHRH).
Figure 4
Figure 4
MD simulation properties: molecular dynamic simulation graphs of wild-type, mutant, and their docked complexes with GHRH.
See this image and copyright information in PMC

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