Table of Contents 22-1

RMRP is an Essential Cell Growth Regulator

Anauxetic (to not let grow) dysplasia (OMIM 607095) is a rare autosomal recessive spondylometaepiphyseal dysplasia characterized by prenatal onset of extreme growth failure combined with mild mental retardation and distinctive skeletal X-ray abnormalities. Growth plate histology suggests a severe disturbance of cell proliferation. Thiel and colleagues studied members of two previously reported families, as well as an unpublished sporadic case of anauxetic dysplasia. (Figure)

Genome-wide homozygosity mapping in a large consanguineous family localized the gene to an 18.7 cM region on chromosome 9p13-21. Fine mapping narrowed the critical region to 17.1 cM, which contains 77 known genes, one of which is RMRP, which encodes the untranslated RNA subunit of the ribonucleoprotein endoribonuclease, RNA MRP. RMRP mutations are found in cartilage hair hypoplasia (CHH) as well as in metaphyseal dysplasia without hypotrichosis (MDWH). Mutation analysis in this study revealed a homozygous insertional mutation in the consanguineous family and compound heterozygous mutations in the second family and the sporadic patient with anauxetic dysplasia. The same mutant allele was detected in the second family and in the sporadic case, and haplotype analysis confirmed a common ancestral haplotype, a founder effect. Thus, anauxetic dysplasia is allelic with CHH and MDWH, both of which are also recessive disorders.

Next, the authors carried out functional studies to try to understand the consequences of the RMRP mutations. First, they documented that expression of RMRP was substantially reduced compared to controls in lymphocytes and fibroblasts from patients in the non-consanguinous family. They then showed that the growth rate of very poorly growing fibroblasts from an affected member of this family could be increased dramatically by transfecting the cells with normal (wild-type) RMRP. They also demonstrated defective cleavage of 5.8S rRNA, a predicted function of RMRP, in this patient’s lymphocytes and fibroblasts and that it could be corrected by introducing wild type RMRP into the patient’s cells.

They next compared RMRP harboring anauxetic mutations to wild type RMRP and RMRP with the common ancestral CHH mutation in several functional assays. In most assays, values for RMRP-CHH were intermediate between values for RMRP-anauxetic dysplasia and wild type RMRP. However, interestingly, the CHH mutation was associated with increased cyclin B2 levels suggesting disturbed cyclin B2 mRNA degradation that was not observed for the anauxetic dysplasia mutations. Degradation of this mRNA is a predicted function of RMRP from studies of it’s yeast homolog - nme1. Cyclical variations in cyclin levels resulting from synthesis and degradation are essential for the control of mitosis. Degradation of cyclin B2 by RMRP therefore provides a means by which it can influence the cell cycle and a consequently mechanism by which RMRP mutations can disturb mitosis.

In conclusion, the authors suggested that two of the functions of RMRP - degradation of rRNA that is required for ribosomal assembly and degradation of mRNAs including cyclin B2 mRNA – are affected differently by CHH and anauxetic mutations. The CHH mutation appears to adversely affect both functions but only moderately, whereas the anauxetic dysplasia mutations do not affect cyclin B2 mRNA levels, but severely incapacitate ribosomal assembly through their adverse effect on ribosomal RNA processing.

Thiel CT , Horn D, Zabel B, et al. Severely incapacitating mutations in patients with extreme short stature identify RNA-processing endoribonuclease RMRP as an essential cell growth regulator. Am J Hum Genet. 2005:77;795 - 806.

Clinical and x-ray characteristics of anauxetic dysplasia. A, far left and near left, Patient, aged 16.5, showing severe short stature with hyperlordosis (height of 74 cm). Upper right, X-ray of the left arm at age 7, showing extremely retarded carpal ossification corresponding to ~ 3 mo bone age, as well as short and broad tubular bones. Lower right, X-ray of spine and pelvis at age 7, showing decreased vertical dimension of the ilia, unossified femoral necks, and small, irregular capital femoral epiphyses. B, X-rays of lower extremities at age 7 mo (top) and pelvis at age 2 (bottom) of patient 3, showing δ-shaped metaphyses with irregular borders and pelvic changes similar to those in panel A.

Reprinted with permission. Thiel CT , et al. Am J Hum Genet 77:795-806, 2005. Copyright © 2005. All rights reserved.

First Editor’s Comment: This paper provides novel insight into how RMRP functions are disturbed by CHH and anauxetic mutations and how differences in mutation type might explain differences in the respective clinical phenotypes. It will be interesting to watch this story continue to unfold.

William A. Horton, MD

Second Editor’s Comment: With the identification of RMRP, an essential regulatory element of chondrocyte growth has been recognized. The mutations in RMRP in anauxetic dysplasia have a profound adverse effect on ribosome synthesis as defective endonuclease cleavage of a precursor subunit impairs ribosome assembly and hence protein synthesis. The more substantial the loss of function mutation in RMRP, the greater is the clinical expression of disease. Thus the manifestations of anauxetic dysplasia, cartilage hair hypoplasia, and metaphyseal dysplasia without hypotrichosis differ only in degree. One speculates that polymorphic variations of RMRP may influence adult stature in normal subjects.

Allen W. Root, MD