Achondroplasia Gene Research Articles

The Impact of Large-Scale Genomic Methods in Orthopaedic Disorders: Insights from Genome-Wide Association Studies

Genetic studies of orthopaedic conditions, particularly those of childhood onset, enjoyed many successes in the early days of disease gene discovery. Some of the earliest high-profile discoveries centered on diseases with skeletal manifestations, such as neurofibromatosis1,2, achondroplasia3,4, and brachydactyly5-8. These successes were largely attributable to the availability of extended families with multiple affected members. Multigenerational families were informative in linkage mapping, also called inheritance mapping (Table I). Linkage mapping is an unbiased approach that seeks to identify genomic regions and genes that are inherited or “linked” among all affected members of the family. Linkage mapping proved particularly powerful for solving diseases that (1) have Mendelian inheritance, being caused by a single mutation in a family; (2) display high penetrance, such that essentially all family members with the mutation show the disease; and (3) are prevalent enough to permit the identification of several extended families. Linking a disease to a specific region of the genome was an important milestone for many early genetic studies, with such highlights as the mapping of the neurofibromatosis-1 gene (NF1) to chromosome 17q11.2 and the achondroplasia gene (FGFR3, which encodes fibroblast growth factor receptor 3) to 4p16.3. Once linkage mapping focused attention on a particular genomic region, the next major step in discovery was analysis of the region to identify the culprit gene harboring a disease-causing mutation. This process was labor and resource-intensive because linked regions were typically large and poorly annotated and encoded numerous genes9. A now classic, and celebrated, example of the immense effort required to find a disease mutation is the almost ten-year search for the Huntington disease gene10. Nevertheless, the combination of linkage mapping and individual gene sequencing in families, traditionally called positional cloning, was highly …

Cytokines in bone diseases. FGF receptor signaling and achondroplasia/hypochondroplasia

FGFR3 has been establishing its position in growth plate cartilage after the identification as a responsible gene for achondroplasia. The major pathway of the pathogenesis in achondroplasia is the suppression of PTHrP-PTHR system, which is mainly mediated by ERK activation induced by constitutive active FGFR3. However, intracellular signaling system in FGFR3 is complex and the molecular pathogenesis of achondroplasia and related disorders has not been fully clarified. Especially, recently found human loss-of-function mutations in newly identified syndromes casted novel findings in the relation between phenotype and receptor function. In this review, I summarized recent consensus in the pathogenesis of FGFR3 related chondrodysplasia.

Predominance of the mutation at 1138 of the cDNA for the fibroblast growth factor receptor 3 in Japanese patients with achondroplasia.

Fibroblast growth factor receptor 3 (FGFR3) has recently been identified as a putative gene for achondroplasia. Since a guanine to adenine mutation at 1138 of the cDNA for FGFR3 had been identified in most of the patients in Western population, we examined 13 Japanese patients to see if they also share the same mutation. Specific endonuclease digestion of the amplified coding sequence for the transmembrane domain of the FGFR3 revealed that the 12 patients have the G to A change at 1138, while the other had the G to C substitution at the same point, both of which result in G380A substitution. As far as we studied, the homogeneity of the point mutation at 1138 is also authentic to Japanese patient as well as Western patients.

Effect of paternal age in achondroplasia, thanatophoric dysplasia, and osteogenesis imperfecta

The paternal ages of nonfamilial cases of achondroplasia (AC) (n = 78), thanatophoric dysplasia (TD) (n = 64), and osteogenesis imperfecta (OI) (n = 106), were compared with those of matched controls, from an Italian Indagine Policentrica Italiana sulle Malformazioni Congenite and a South American Estudio Colaborativo Latinoamericano de Malformaciones Congénitas series. The degree of paternal age effect on the origin of these dominant mutations differed among the three conditions. Mean paternal age was highly elevated in AC, 36.30 +/- 6.74 years in the IPIMC, and 37.19 +/- 10.53 years in the ECLAMC; less consistently elevated in TD, 33.60 +/- 7.08 years in the IPIMC, and 36.41 +/- 9.38 years in the ECLAMC; and only slightly elevated in OI in the ECLAMC, 31.15 +/- 9.25 years, but not in the IPIMC, 32.26 +/- 6.07 years. Increased maternal age or birth order in these conditions disappeared when corrected for paternal age. Approximately 50% of AC and TD cases, and only 30% of OI cases, were born to fathers above age 35 years. For AC and TD, the increase in relative incidence with paternal age fitted an exponential curve. The variability of paternal age effect in these new mutations could be due, among other reasons, to the high proportion of germ-line mosaicism in OI parents, or to the localization of the AC gene, mapped to the 4p16.3 region, in the neighborhood of an unstable DNA area.

Information Update on Achondroplasia

Last month guidelines for the care of children with Achondroplasia were published in Pediatrics (1995;95:443-451). They represent three years of work by the American Academy of Pediatrics (AAP) Committee on Genetics. They are already out of date!! The field of molecular genetics is moving at an amazing pace. While the guidelines were being developed, the gene for Achondroplasia was mapped and sequenced and the specific defect identified. Because the mutation is very specific and very consistent in Achondroplasia [most diseases have many different mutations in the responsible gene(s)], it has been possible to develop an exquisitely precise diagnostic test very rapidly.

Health Supervision for Children With Achondroplasia

This set of guidelines is designed to assist the pediatrician in caring for children with achondroplasia confirmed by radiographs and physical features. Although pediatricians usually first see children with achondroplasia during infancy, occasionally they are called on to advise the pregnant woman who has been informed of the prenatal diagnosis of achondroplasia or asked to examine the newborn to help establish the diagnosis. Therefore, these guidelines offer advice for these situations as well. Achondroplasia is the most common form of disproportionate short stature.1 The diagnosis is based on very specific features on the radiographs, which include a contracted base of the skull, a square shape to the pelvis with a small sacrosciatic notch, short pedicles of the vertebrae, rhizomelic (proximal) shortening of the long bones, trident hands, a normal length trunk, proximal femoral radiolucency, and, by mid-childhood, a characteristic chevron shape of the distal femoral epiphysis. Hypochondroplasia and thanatophoric dysplasia are part of the differential diagnosis, but achondroplasia can be distinguished from these because the changes in hypochondroplasia are milder and the changes in thanatophoric dysplasia are much more severe and invariably lethal. Achondroplasia is an autosomal dominant disorder, but approximately 75% of cases represent new dominant mutations. The gene for achondroplasia has recently been found. Achondroplasia is due to a change in the genetic information for fibroblast growth factor receptor 3.2,3 Almost all of the mutations have been found to occur in exactly the same spot. Now that the gene has been found and the mutation known, potential therapies and diagnostic methodologies are likely to be developed.

A common FGFR3 gene mutation is present in achondroplasia but not in hypochondroplasia

Achondroplasia is the most common type of genetic dwarfism. It is characterized by disproportionate short stature and other skeletal anomalies resulting from a defect in the maturation of the chondrocytes in the growth plate of the cartilage. Recent studies mapped the achondroplasia gene on chromosome region 4p16.3 and identified a common mutation in the gene encoding the fibroblast growth factor receptor 3 (FGFR3). In an analysis of 19 achondroplasia families from a variety of ethnic backgrounds we confirmed the presence of the G380R mutation in 21 of 23 achondroplasia chromosomes studied. In contrast, the G380R mutation was not found in any of the 8 hypochondroplasia chromosomes studied. Furthermore, linkage studies in a 3-generation family with hypochondroplasia show discordant segregation with markers in the 4p16.3 region suggesting that at least some cases of hypochondroplasia are caused by mutations in a gene other than FGFR3.

Medical genetics: advances in brief: Localization of the achondroplasia gene to the distal 2-5 Mb of human chromosome 4p

Medical genetics: advances in brief: Localization of the achondroplasia gene to the distal 2-5 Mb of human chromosome 4p

Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia

Achondroplasia (ACH) is the most common genetic form of dwarfism. This disorder is inherited as an autosomal dominant trait, although the majority of cases are sporadic. A gene for ACH was recently localized to 4p 16.3 by linkage analyses. The ACH candidate region includes the gene encoding fibroblast growth factor receptor 3 (FGFR3), which was originally considered as a candidate for the Huntington's disease gene. DNA studies revealed point mutations in the FGFR3 gene in ACH heterozygotes and homozygotes. The mutation on 15 of the 16 ACH-affected chromosomes was the same, a G→A transition, at nucleotide 1138 of the cDNA. The mutation on the only ACH-affected chromosome 4 without the G→A transition at nucleotide 1138 had a G→C transversion at this same position. Both mutations result in the substitution of an arginine residue for a glycine at position 380 of the mature protein, which is in the transmembrane domain of FGFR3.

The gene for achondroplasia maps to the telomeric region of chromosome 4p

Achondroplasia is the most common type of genetic dwarfism. It is characterized by disproportionate short stature and other skeletal anomalies resulting from a defect in the maturation of the chondrocytes in the growth plate of the cartilage. We have now mapped the achondroplasia gene near the telomere of the short arm of chromosome 4 (4p16.3), by family linkage studies using 14 pedigrees. A positive lod score of z = 3.35 with no recombinants was obtained with an intragenic marker for IDUA. This localization will facilitate the positional cloning of the disease gene.

Localization of the achondroplasia gene to the distal 2.5 Mb of human chromosome 4p.

Achondroplasia has been mapped to 4p16.3 using 18 multigenerational families with achondroplasia and 10 short tandem repeat polymorphic markers from this region. No evidence of genetic heterogeneity was found. Analysis of a recombinant family localizes the achondroplasia locus to the 2.5 Mb region between D4S43 and the telomere. Multipoint linkage analysis favors placement telomeric of D4S412. The establishment of closely linked markers will facilitate positional cloning of the achondroplasia gene and permit prenatal diagnosis of homozygous achondroplasia for at risk couples.

Molecular analysis of a patient with neurofibromatosis 1 and achondroplasia

The gene for von Recklinghausen neurofibromatosis (NF1) is on proximal 17q; the location of the gene for achondroplasia (ACH) is unknown. We have begun a molecular analysis of a patient with mental retardation, NF1 and ACH, a clinical presentation suggestive of a contiguous gene syndrome. In addition, this individual has a 47,XYY chromosome constitution. To define a possible chromosome 17 deletion, we investigated the copy number of DNA sequences linked to NF1 with conventional and pulsed-field gel electrophoresis (PFGE). We found no evidence for a deletion on chromosome 17. These results make it unlikely that this patient harbors a single deletion in the NF1 region causing both NF1 and ACH and suggest different mechanisms for the de novo occurrence of 2 autosomal dominant disorders in this individual.

The achondroplasia gene is not linked to the locus for neurofibromatosis 1 on chromosome 17

We have investigated genetic linkage of von Recklinghausen neurofibromatosis (NF1) and achondroplasia (ACH) using chromosome-17 markers that are known to be linked to NF1. Physical proximity of the two loci was suggested by the report of a patient with mental retardation and the de novo occurrence of both NF1 and ACH. Since the chance of de novo occurrence of these two disorders in one individual is 1 in 600 million, this suggested a chromosomal deletion as a single unifying molecular event and also that the ACH and NF1 loci might be physically close. To test this, we performed linkage analysis on a three-generation family with ACH. We used seven DNA probes that are tightly linked to the NF1 locus, including DNA sequences that are known to flank the NF1 locus on the centromeric and telomeric side. We detected two recombinants between the ACH trait and markers flanking the NF1 locus. In one recombinant, the flanking markers themselves were nonrecombinant. Multi-point linkage analysis excluded the ACH locus from a region surrounding the NF1 locus that spans more than 15 cM (lod score less than -2). Therefore, analysis of this ACH pedigree suggests that the ACH locus is not linked to the NF1 locus on chromosome 17.

Molecular genetic studies in achondroplasia.

The clinical phenotype of achondroplasia has been extensively covered by other speakers in this symposium. In summary, the condition is a dominantly inherited form of rhizomelic dwarfism with an incidence estimated between 1/20,000 and 1/50,000 live births (1). The mutation presents as a primary disorder of bone growth; manifestations in other systems, such as the neuroaxis (2), appear to result from bony impingement. Because the achondroplasia gene acts principally at the growth plate, those gene products which are known to be structurally crucial to cartilage have naturally come under investigation in the search for the cause of achondroplasia.

Observations of growth plate development in achondroplastic (cn/cn) mice.

The autosomal recessive gene for achondroplasia (cn) in the homozygous condition inhibits the growth of the cartilaginous skeleton in mice. Changes in the width of the proximal growth plate of the tibia and the caudal vertebrae and in the number of proliferative and hypertrophic cells were recorded in normal and achondroplastic (cn/cn) mice during the first 30 neonatal days. In normal mice as in achondroplastics, the width of the cartilaginous growth plate decreased progressively with increasing age. The proliferative zone of cn/cn mice was similar in structure to that of normal mice and showed no significant difference. Hypertrophied cartilage was less wide and there were fewer hypertrophic cells at the epiphyseal plates than found in normal mice. The data of the present study show that retarded longitudinal bone growth in cn/cn mice is due to reduced hypertrophy of the chondrocytes.

Observations suggesting allelism of the achondroplasia and hypochondroplasia genes.

It is argued that there are at least two alleles at the achondroplasia locus: one responsible for classic achondroplasia and one responsible for hypochondroplasia. Homozygosity for the achondroplasia gene produces a lethal skeletal dysplasia; homozygosity for hypochondroplasia has not been described. We report here a child considered to be a genetic compound for the achondroplasia and hypochondroplasia alleles.

Achondroplasia and thanatophoric dwarfism in the newborn.

Out of a total of 64,000 births in St. Mary's Hospital, Manchester, 17 were originally diagnosed as having achondroplasia. When the diagnosis was reviewed, 10 of these infants proved to be thanatophoric dwarfs, 3 had inherited achondroplasia, 1 was apparently a mutant achondroplastic, while 3 others had other forms of non‐achondroplastic chondrodystrophy. All 10 thanatophoric dwarfs but only one other child in the series were still‐born. It is concluded that both the birth rate and the perinatal mortality rate for achondroplasia are much lower than was previously believed.The clinical features of 10 infants with thanatophoric dwarfism in this series are reviewed and a high incidence of associated defects noted. There was an excess of affected males and one pair of affected sibs occurred suggesting autosomal recessive inheritance, with sex‐limitation or early loss of female embryos, in thanatophoric dwarfism.The implications of this diagnostic heterogeneity are important in counselling parents of apparently achondroplastic infants.The necessity for postulating a high mutation rate to the achondroplasia gene depended upon the assumption that about 80% of such infants died. The results reported here have suggested that most of this mortality is accounted for by thanatophoric dwarfs and consequently it is no longer necessary to postulate a mutation rate greater than 1:100,000 at most in achondroplasia.