Severely Incapacitating Mutations in Patients with Extreme Short Stature Identify RNA-Processing Endoribonuclease RMRP as an Essential Cell Growth Regulator

Abstract

The growth of an individual is deeply influenced by the regulation of cell growth and division, both of which also contribute to a wide variety of pathological conditions, including cancer, diabetes, and inflammation. To identify a major regulator of human growth, we performed positional cloning in an autosomal recessive type of profound short stature, anauxetic dysplasia. Homozygosity mapping led to the identification of novel mutations in the RMRP gene, which was previously known to cause two milder types of short stature with susceptibility to cancer, cartilage hair hypoplasia, and metaphyseal dysplasia without hypotrichosis. We show that different RMRP gene mutations lead to decreased cell growth by impairing ribosomal assembly and by altering cyclin-dependent cell cycle regulation. Clinical heterogeneity is explained by a correlation between the level and type of functional impairment in vitro and the severity of short stature or predisposition to cancer. Whereas the cartilage hair hypoplasia founder mutation affects both pathways intermediately, anauxetic dysplasia mutations do not affect B-cyclin messenger RNA (mRNA) levels but do severely incapacitate ribosomal assembly via defective endonucleolytic cleavage. Anauxetic dysplasia mutations thus lead to poor processing of ribosomal RNA while allowing normal mRNA processing and, therefore, genetically separate the different functions of RNase MRP.

Ribosomopathies: human disorders of ribosome dysfunction

“…63 In contrast, cells with the CHH founder RMRP mutation had significantly increased levels of cyclin B2 mRNA. 63 Cyclin B2 is known to contribute to chromosomal instability through alterations of the mitotic spindle checkpoint, 64 which suggests another possible explanation for the bone marrow dysfunction seen in CHH. Recent work by Maida et al has revealed a connection between RMRP and TERT.…”

“…63 Thiel et al showed that, in cells overexpressing the RMRP mutants seen in anauxetic dysplasia, there were decreased cyclin A2 levels. 63 In contrast, cells with the CHH founder RMRP mutation had significantly increased levels of cyclin B2 mRNA.…”

“…63 Thiel et al showed that, in cells overexpressing the RMRP mutants seen in anauxetic dysplasia, there were decreased cyclin A2 levels. 63 In contrast, cells with the CHH founder RMRP mutation had significantly increased levels of cyclin B2 mRNA. 63 Cyclin B2 is known to contribute to chromosomal instability through alterations of the mitotic spindle checkpoint, 64 which suggests another possible explanation for the bone marrow dysfunction seen in CHH.…”

“…65 The clinical heterogeneity seen in CHH and in anauxetic dysplasia might be attributable to differences in the magnitude and type of alteration in ribosomal assembly, telomere dysfunction, and cyclin B2 levels caused by various RMRP mutations. 63 …”

Identification of novel RMRP mutations and specific founder haplotypes in Japanese patients with cartilage-hair hypoplasia

“…To date, 73 RMRP mutations have been reported (Ridanpaa et al 2001(Ridanpaa et al , 2002Bonafe et al 2002Bonafe et al , 2005Nakashima et al 2003;Kuijpers et al 2003;Harada et al 2005;Hermanns et al 2005;Thiel et al 2005). The 70A>G mutation is the most prevalent; it comprises 92% of mutations seen in the Finnish population and is commonly seen in other populations (Ridanpaa et al 2002).…”