PubMed · 13350782
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C JIMENEZ DIAZ, E LOPEZ GARCIA. 1956-05-31. [Epiphysialis multiplex dystrophy].. https://pubmed.ncbi.nlm.nih.gov/13350782/
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We generated transgenic mice that express a constitutively active mutant of MEK1 in chondrocytes. These mice showed a dwarf phenotype similar to achondroplasia, the most common human dwarfism, caused by activating mutations in FGFR3. These mice displayed incomplete hypertrophy of chondrocytes in the growth plates and a general delay in endochondral ossification, whereas chondrocyte proliferation was unaffected. Immunohistochemical analysis of the cranial base in transgenic embryos showed reduced staining for collagen type X and persistent expression of Sox9 in chondrocytes. These observations indicate that the MAPK pathway inhibits hypertrophic differentiation of chondrocytes and negatively regulates bone growth without inhibiting chondrocyte proliferation. Expression of a constitutively active mutant of MEK1 in chondrocytes of Fgfr3-deficient mice inhibited skeletal overgrowth, strongly suggesting that regulation of bone growth by FGFR3 is mediated at least in part by the MAPK pathway. Although loss of Stat1 restored the reduced chondrocyte proliferation in mice expressing an achondroplasia mutant of Fgfr3, it did not rescue the reduced hypertrophic zone, the delay in formation of secondary ossification centers, and the achondroplasia-like phenotype. These observations suggest a model in which Fgfr3 signaling inhibits bone growth by inhibiting chondrocyte differentiation through the MAPK pathway and by inhibiting chondrocyte proliferation through Stat1.
The origin and frequency of spontaneous mutations that occur with age in humans have been a topic of intense discussion. The mechanisms by which spontaneous mutations arise depend on the parental germ line in which a mutation occurs. In general, paternal mutations are more likely than maternal mutations to be base substitutions. This is likely due to the larger number of germ cell divisions in spermatogenesis than in oogenesis. Maternal mutations are more often chromosomal abnormalities. Advanced parental age seems to influence some mutations, although it is not a factor in the creation of others. In this review, we focus on patterns of paternal bias and age dependence of mutations in different genetic disorders, and the various mechanisms by which these mutations arise. We also discuss recent data on age and the frequency of these mutations in the human male germ line and the impact of these data on this field of research.
Achondroplasia is a skeletal dysplasia that manifests as short stature. Impairment and complications range over many disciplines including orthopedics, pediatrics, neurology, and otolaryngology. The major impairments of the extremities are short limbs, limited elbow and hip extension, and knee and leg deformities that can cause disabilities in arm function and locomotion. Hydrocephalus, a narrow foramen magnum, spinal deformity, and spinal canal stenosis can cause neurological problems, leading to disabilities in locomotion, communication, and learning. Malfunctions of the otolaryngeal system such as otitis media, upper respiratory obstruction, deafness, speech delay, and malocclusion are interrelated and can also lead to disabilities in communication and learning. Although such disabilities may cause social handicaps, most children receive a normal education. Their social maturity scale is comparable to that of normal children, but their scale of locomotion is not. The reported occupational level of female adult patients is lower than that of their unaffected siblings. When managing patients, orthopedists should consider the overall aspects of achondroplasia, including natural development and complications other than orthopedic factors.