Defective minor spliceosome mRNA processing results in isolated familial growth hormone deficiency

Abstract

The molecular basis of a significant number of cases of isolated growth hormone deficiency remains unknown. We describe three sisters affected with severe isolated growth hormone deficiency and pituitary hypoplasia caused by biallelic mutations in the RNPC3 gene, which codes for a minor spliceosome protein required for U11/U12 small nuclear ribonucleoprotein (snRNP) formation and splicing of U12-type introns. We found anomalies in U11/U12 di-snRNP formation and in splicing of multiple U12-type introns in patient cells. Defective transcripts include preprohormone convertases SPCS2 and SPCS3 and actin-related ARPC5L genes, which are candidates for the somatotroph-restricted dysfunction. The reported novel mechanism for familial growth hormone deficiency demonstrates that general mRNA processing defects of the minor spliceosome can lead to very narrow tissue-specific consequences.

Disrupted minor intron splicing is prevalent in Mendelian disorders

“…This was modeled in two different mouse models, through knockout of Rnpc3 and Rnu11 (Baumgartner et al., 2018; Doggett et al., 2018). Germline ablation of both Rnpc3 and Rnu11 resulted in embryonic lethality, again suggesting that the variants observed in minor spliceosome‐related diseases such as IGHD are hypomorphic (Argente et al., 2014; Baumgartner et al., 2018; Doggett et al., 2018). Ablation of Rnpc3 in adult mice resulted in severe gastrointestinal defects, as well as a reduction of peripheral lymphocytes and platelets (Doggett et al., 2018).…”

“…Ablation of Rnpc3 in adult mice resulted in severe gastrointestinal defects, as well as a reduction of peripheral lymphocytes and platelets (Doggett et al., 2018). While the latter phenotype resembles some of the immunological symptoms that individuals with Roifman syndrome experience, gastrointestinal defects are generally not found in individuals with IGHD (Argente et al., 2014). This may be due to a change in the expression pattern of Rnpc3 from embryonic development to adulthood.…”

“…Moreover, pathogenic variants in RNU12 , which encodes the U12 snRNA, have been linked to early onset cerebellar ataxia (Elsaid et al., 2017). Finally, variants in RNPC3 (OMIM: 618016), a minor spliceosome‐specific protein that is part of the U12 small nuclear ribonucleoprotein (snRNP), have been associated with isolated growth hormone deficiency (IGHD) (Argente et al., 2014). Finally, somatic mutations in ZRSR2 , a protein component of both the major and minor spliceosome, have been shown to predominately affect minor intron splicing, resulting in myelodysplastic syndrome (Madan et al., 2015).…”

“…The autosomal recessive inheritance pattern of minor spliceosome‐related diseases suggests that these pathogenic variants result in a loss‐of‐function (Argente et al., 2014; Edery et al., 2011; Elsaid et al., 2017; Farach et al., 2018; He et al., 2011; Merico et al., 2015). Consequently, this would result in the aberrant splicing and expression of minor intron‐containing genes (MIGs).…”

Establishing intellectual disability as the key feature of patients with biallelic RNPC3 variants

“…Recently, two families with affected members showing severe proportionate short stature were shown to carry biallelic variants of the RNPC3 gene: the first family with a nonsense variant (c.1504C>T, p.R502X) and a non‐synonymous variant (c.1420C>A, p.P474T) (Argente et al, 2014; Martos‐Moreno et al, 2018), and the second family with a nonsense variant (c.259C>T, p.Q87X) and a non‐synonymous variant (c.443G>C, p.G148A) (Verberne et al, 2020), respectively. RNPC3 encodes the 65K protein component of U11/U12 di‐snRNP, which constitutes the minor spliceosome (Will et al, 2004) which recognize 5′ splice sites (5′ss) and branch point sequences (BPS) (Turunen et al, 2013).…”