ESPEYB19 1. Pituitary and Neuroendocrinology Genetics (5 abstracts)
1.7. Pathogenic variants in RNPC3 are associated with hypopituitarism and primary ovarian insufficiency
Akin L , Rizzoti K , Gregory LC , Corredor B , Le Quesne Stabej P , Williams H , Buonocore F , Mouilleron S , Capra V , McGlacken-Byrne SM , Martos-Moreno GÁ , Azmanov DN , Kendirci M , Kurtoglu S , Suntharalingham JP , Galichet C , Gustincich S , Tasic V , Achermann JC , Accogli A , Filipovska A , Tuilpakov A , Maghnie M , Gucev Z , Gonen ZB , Pérez-Jurado LA , Robinson I , Lovell-Badge R , Argente J & Dattani MT
Genet Med. 2022 Feb;24(2):384-397. doi: 10.1016/j.gim.2021.09.019. PMID: 34906446.
Brief Summary: This study extends the phenotypes related to pathogenic biallelic RNPC3 variants to cover primary ovarian insufficiency (POI) in combination with the previously associated growth hormone deficiency (GHD).
The authors report 15 patients from 9 pedigrees with severe GHD, hypoprolactinemia, variable thyrotropin (TSH) deficiency, and also POI in 8/9 affected females. POI manifested as stalled puberty, whereas affected males had normal pubertal development and gonadal function. Severe biochemical GHD was present in all patients, but 2 male patients exhibited normal growth while off exogenous growth hormone supplementation. Anterior pituitary hypoplasia was noted in 13 patients, and 4 patients from different pedigrees were diagnosed with motor neuropathy.
Next generation sequencing, followed by Sanger sequencing, revealed biallelic pathogenic-assessed variants in RNPC3 in all patients, including a novel homozygous missense variant c.1449A>T (p.Leu483Phe) in 8 patients from 5 consanguineous Turkish pedigrees. RNPC3 encodes a protein component of minor spliceosome and represents a novel genetic mechanism causative for POI.
Using in situ hybridization, the authors showed that RNPC3/Rnpc3 is expressed in multiple central nervous system areas, including the hypothalamus and Rathke’s pouch in both human and mouse. Rnpc3 was also expressed in the ovaries of adult mice. The data were partially supported by the phenotype of CRISPR-Cas9 generated Rnpc3 p.Leu483Phe/p.Leu483Phe mouse model: the female, but not male mice had GHD. There was no sign of POI in young mice.
To summarize, this study describes patients with biallelic pathogenic RNPC3 variants, manifesting with variable pituitary hormone deficiency, and POI. Indeed, the disruption of both central and peripheral endocrine functions is quite unusual in monogenic endocrine disorders. Future functional studies are needed to elucidate the role of RNPC3 variants for the motor neuropathy phenotype.
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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