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Review
. 2021 Apr;24(2):229-241.
doi: 10.1007/s11102-020-01101-8. Epub 2020 Nov 13.

Congenital hypopituitarism in two brothers with a duplication of the 'acrogigantism gene' GPR101: clinical findings and review of the literature

Melitza S M Elizabeth #  1   2   3 , Annemieke J M H Verkerk #  4 , Anita C S Hokken-Koelega  5   6   7 , Joost A M Verlouw  4 , Jesús Argente  8   9   10   11 , Roland Pfaeffle  12 , Sebastian J C M M Neggers  4 , Jenny A Visser  4 , Laura C G de Graaff  4   7
Affiliations
Review

Congenital hypopituitarism in two brothers with a duplication of the 'acrogigantism gene' GPR101: clinical findings and review of the literature

Melitza S M Elizabeth et al. Pituitary. 2021 Apr.

Abstract

Purpose: Congenital hypopituitarism (CH) can cause significant morbidity or even mortality. In the majority of patients, the etiology of CH is unknown. Understanding the etiology of CH is important for anticipation of clinical problems and for genetic counselling. Our previous studies showed that only a small proportion of cases have mutations in the known 'CH genes'. In the current project, we present the results of SNP array based copy number variant analysis in a family with unexplained congenital hypopituitarism.

Methods: DNA samples of two affected brothers with idiopathic CH and their mother were simultaneously analyzed by SNP arrays for copy number variant analysis and Whole Exome Sequencing (WES) for mutation screening. DNA of the father was not available.

Results: We found a 6 Mb duplication including GPR101 and SOX3 on the X-chromosome (Xq26.2-q27.1) in the two siblings and their mother, leading to 2 copies of this region in the affected boys and 3 copies in the mother. Duplications of GPR101 are associated with X-linked acrogigantism (the phenotypic 'opposite' of the affected brothers), whereas alterations in SOX3 are associated with X-linked hypopituitarism.

Conclusion: In our patients with hypopituitarism we found a 6 Mb duplication which includes GPR101, a gene associated with X- linked gigantism, and SOX3, a gene involved in early pituitary organogenesis that is associated with variable degrees of hypopituitarism. Our findings show that in duplications containing both GPR101 and SOX3, the growth hormone deficiency phenotype is dominant. This suggests that, if GPR101 is duplicated, it might not be expressed phenotypically when early patterning of the embryonic pituitary is affected due to SOX3 duplication. These results, together with the review of the literature, shed a new light on the role of GPR101 and SOX3 in pituitary function.

Keywords: Acromegaly; G-protein coupled receptor; Gene duplication; Pituitary gland; Transcription factors.

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Figures

Fig. 1
Fig. 1
SNP array results of the two brothers and their mother. LogR ratios and B-allele frequencies (BAF) are indicated. Duplications are shown between vertical bars for a the mother, b and c the affected brothers
Fig. 2
Fig. 2
a Overview of 70 genes included in the duplicated region. b All duplications and deletions found in the literature involving GPR101 and SOX3
See this image and copyright information in PMC

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