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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reported families, as well as an unpublished sporadic case of anauxetic dysplasia.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.
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
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Current GGH - Vol. 24 No. 1
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