Response to growth hormone in patients with
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            mutations

Martos‐Moreno, Gabriel Ángel; Travieso‐Suárez, Lourdes; Pozo‐Román, Jesús; Muñoz-Calvo, M.T.; Chowen, Julie A.; Frilander, Mikko J.; Pérez-Jurado, Luís A.; Hawkins, Federico; Argente, Jesús

doi:10.15252/emmm.201809143

Cited by 6 publications

(2 citation statements)

References 9 publications

(12 reference statements)

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“…Some areas of the genome have limited capture by whole exome sequencing, making it difficult to go from a diagnosis based on phenotype and medical background to proof from genotype. Therefore, next-generation sequencing techniques, such as targeting exome sequencing, are being developed, to target specific collections of candidate genes with the use of chromosomal microarrays to detect copy number variations (16, 111). Such techniques can be directed to make a specific diagnosis, while whole exome and whole genome sequencing may be more useful for research purposes to identify new genetic variations associated with specific conditions: identifying the genes involved in combined pituitary hormone deficiency may be more useful as a scientific interest to provide new insights into pathogenesis and novel treatment strategies; identifying the genes involved in Turner syndrome will be more useful from a diagnostic point of view, when appropriate genetic counseling and treatment monitoring can be carried out; and detecting the genes involved in GH resistance could be useful for both scientific research and for identifying potential clinical consequences.…”

Section: Discussionmentioning

confidence: 99%

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Genetics of Growth Disorders—Which Patients Require Genetic Testing?

et al. 2019

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The second 360° European Meeting on Growth Hormone Disorders, held in Barcelona, Spain, in June 2017, included a session entitled Pragmatism vs. Curiosity in Genetic Diagnosis of Growth Disorders, which examined current concepts of genetics and growth in the clinical setting, in terms of both growth failure and overgrowth. For patients with short stature, multiple genes have been identified that result in GH deficiency, which may be isolated or associated with additional pituitary hormone deficiencies, or in growth hormone resistance, primary insulin-like growth factor (IGF) acid-labile subunit deficiency, IGF-I deficiency, IGF-II deficiency, IGF-I resistance, and primary PAPP-A2 deficiency. While genetic causes of short stature were previously thought to primarily be associated with the GH–IGF-I axis, it is now established that multiple genetic anomalies not associated with the GH–IGF-I axis can result in short stature. A number of genetic anomalies have also been shown to be associated with overgrowth, some of which involve the GH–IGF-I axis. In patients with overgrowth in combination with an intellectual disability, two predominant gene families, the epigenetic regulator genes, and PI3K/AKT pathway genes, have now been identified. Specific processes should be followed for decisions on which patients require genetic testing and which genes should be examined for anomalies. The decision to carry out genetic testing should be directed by the clinical process, not merely for research purposes. The intention of genetic testing should be to direct the clinical options for management of the growth disorder.

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Section: Discussionmentioning

confidence: 99%

“…The growth failure was post-natal and proportionate, with only mild microcephaly, anterior pituitary hypoplasia, and normal psychomotor development. GH treatment of these patients was effective, despite severe short stature and late initiation of treatment (16).…”

Section: Genetic Testing For Factors Associated With Short Staturementioning

confidence: 99%

Genetics of Growth Disorders—Which Patients Require Genetic Testing?

et al. 2019

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Expanding the phenotype of biallelic RNPC3 variants associated with growth hormone deficiency

Verberne

Faries

Mannens

et al. 2020

American J of Med Genetics Pt A

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Pathogenic variants in components of the minor spliceosome have been associated with several human diseases. Recently, it was reported that biallelic RNPC3 variants lead to severe isolated growth hormone deficiency and pituitary hypoplasia. The RNPC3 gene codes for the U11/U12‐65K protein, a component of the minor spliceosome. The minor spliceosome plays a role in the splicing of minor (U12‐type) introns, which are present in ~700–800 genes in humans and represent about 0.35% of all introns. Here, we report a second family with biallelic RNPC3 variants in three siblings with a growth hormone deficiency, central congenital hypothyroidism, congenital cataract, developmental delay/intellectual deficiency and delayed puberty. These cases further confirm the association between biallelic RNPC3 variants and severe postnatal growth retardation due to growth hormone deficiency. Furthermore, these cases show that the phenotype of this minor spliceosome‐related disease might be broader than previously described.

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

Yamada

Ono

Ishii

et al. 2021

American J of Med Genetics Pt A

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Some mammalian genes contain both major and minor introns, the splicing of which require distinctive major and minor spliceosomes, respectively; these genes are referred to as minor intron containing‐genes. RNPC3 (RNA‐binding domain‐containing protein 3) is one of the proteins that are unique to the minor spliceosome U11/U12 di‐snRNP. Only two families with biallelic pathogenic variants in the RNPC3 gene encoding the protein have been reported so far, and the affected members in both families had proportional short stature. While the affected members of the originally identified family did not have intellectual disability, the patients from the other family exhibited intellectual disability. Here, we report on a patient with severe primordial microcephalic dwarfism and intellectual disability who carried compound heterozygous variants in RNPC3 (NM_017619.3): c.261dup, p.Leu88Thrfs*11 and c.1228T>G, p.Phe410Val. The single nucleotide substitution c.1228T>G had a very high predictive score for pathogenicity: the p.Phe410 residue is highly conserved down to fish. Based on ACMG (American College of Medical Genetics and Genomics) guideline, this non‐synonymous variant was scored as likely pathogenic. This documentation of yet another patient with biallelic RNPC3 variants exhibiting intellectual disability lends further support to the notion that intellectual disability is a key feature of the spectrum of RNPC3‐related disorders.

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Response to growth hormone in patients with RNPC 3 mutations

Abstract: After 6 years of Growth Hormone (GH) therapy, three patients with a defect in minor spliceosome mRNA processing leading to an incompletely understood GH deficit present with excellent auxological response and improvement in the bone mineral density and trabecular bone structure.

Cited by 6 publications

References 9 publications

Genetics of Growth Disorders—Which Patients Require Genetic Testing?

Genetics of Growth Disorders—Which Patients Require Genetic Testing?

Expanding the phenotype of biallelic RNPC3 variants associated with growth hormone deficiency

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

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