Acromesomelic Dysplasia Research Articles

Natriuretic Peptides, Their Receptors, and Cyclic Guanosine Monophosphate-Dependent Signaling Functions

Natriuretic peptides are a family of structurally related but genetically distinct hormones/paracrine factors that regulate blood volume, blood pressure, ventricular hypertrophy, pulmonary hypertension, fat metabolism, and long bone growth. The mammalian members are atrial natriuretic peptide, B-type natriuretic peptide, C-type natriuretic peptide, and possibly osteocrin/musclin. Three single membrane-spanning natriuretic peptide receptors (NPRs) have been identified. Two, NPR-A/GC-A/NPR1 and NPR-B/GC-B/NPR2, are transmembrane guanylyl cyclases, enzymes that catalyze the synthesis of cGMP. One, NPR-C/NPR3, lacks intrinsic enzymatic activity and controls the local concentrations of natriuretic peptides through constitutive receptor-mediated internalization and degradation. Single allele-inactivating mutations in the promoter of human NPR-A are associated with hypertension and heart failure, whereas homozygous inactivating mutations in human NPR-B cause a form of short-limbed dwarfism known as acromesomelic dysplasia type Maroteaux. The physiological effects of natriuretic peptides are elicited through three classes of cGMP binding proteins: cGMP-dependent protein kinases, cGMP-regulated phosphodiesterases, and cyclic nucleotide-gated ion channels. In this comprehensive review, the structure, function, regulation, and biological consequences of natriuretic peptides and their associated signaling proteins are described.

Du Pan syndrome phenotype caused by heterozygous pathogenic mutations in CDMP1 gene

Du Pan syndrome is a rare acromesomelic dysplasia with characteristic clinical and radiographic findings. It is inherited as an autosomal recessive trait. Almost all the patients reported have been from Muslim countries. We report on a female and her child with Du Pan syndrome from a Caucasian, Polish family. Three new heterozygous mutations clustered on one allele of the CDMP1 gene were identified in the affected individuals resulting in the first familial case with dominant Du Pan syndrome. A possible synergistic effect of the cis-acting mutations located in the active domain of the mature CDMP1 protein is likely to be responsible for the clinical expression of the disorder.

Mutations in the Transmembrane Natriuretic Peptide Receptor NPR-B Impair Skeletal Growth and Cause Acromesomelic Dysplasia, Type Maroteaux

The homodimeric transmembrane receptor natriuretic peptide receptor B (NPR-B [also known as guanylate cyclase B, GC-B, and GUC2B]; gene name NPR2) produces cytoplasmic cyclic GMP from GTP on binding its extracellular ligand, C-type natriuretic peptide (CNP). CNP has previously been implicated in the regulation of skeletal growth in transgenic and knockout mice. The autosomal recessive skeletal dysplasia known as "acromesomelic dysplasia, type Maroteaux" (AMDM) maps to an interval that contains NPR2. We sequenced DNA from 21 families affected by AMDM and found 4 nonsense mutations, 4 frameshift mutations, 2 splice-site mutations, and 11 missense mutations. Molecular modeling was used to examine the putative protein change brought about by each missense mutation. Three missense mutations were tested in a functional assay and were found to have markedly deficient guanylyl cyclase activity. We also found that obligate carriers of NPR2 mutations have heights that are below the mean for matched controls. We conclude that, although NPR-B is expressed in a number of tissues, its major role is in the regulation of skeletal growth.

Delineating biologic pathways involved in skeletal growth and homeostasis through the study of rare Mendelian diseases that affect bones and joints

We have found that the secreted glycoprotein, lubricin, is mutated in patients with the autosomal recessive disorder camptodactyly–arthropathy–coxa vara–pericarditis syndrome. To better define lubricin's role in articulating joints we have been studying lubricin knockout mice. Knockout mice recapitulate features observed in patients with camptodactyly–arthropathy–coxa vara–pericarditis, and therefore allow us to learn more about the protein's in vivo function. We find that synoviocytes from knockout mice have different growth characteristics than do wild-type synoviocytes. We also find that the articular cartilage surface in knockout mice loses superficial zone chondrocytes and becomes covered by proteinaceous material. These results indicate that lubricin protects cartilage surfaces and helps regulate synovial cell growth. We had found that Wnt-inducible-secreted protein 3 (WISP3) is mutated in patients with the autosomal recessive disorder progressive pseudorheumatoid dysplasia. Patients with progressive pseudo-rheumatoid dysplasia require joint replacement surgery for what resembles end-stage osteoarthritis by their second decade of life. WISP3 is in very low abundance since we have only been able to detect mRNA by reverse transcription-polymerase chain reaction, and not by northern blot or in situ hybridization. Furthermore, we have not been able to detect endogenous WISP3 protein using a sensitive polyclonal antibody. Therefore, to determine the role of WISP3 in maintaining joints we created Wisp3 knockout mice. Surprisingly these mice did not develop joint failure, but they did seem to have altered timing of their secondary centers of ossification. We are currently exploring whether this altered timing is relevant to the pathogenesis of cartilage failure in human patients. We have been searching for the gene responsible for autosomal recessive acromesomelic dysplasia. This is an interesting disorder because it primarily affects postnatal, rather than prenatal, growth. Also interesting is the fact that many carrier parents of affected individuals appear to have isolated short stature. Consequently, the discovery of the gene responsible for this disease may provide insights into pathways that effect growth.

GDF-5 deficiency in mice alters the ultrastructure, mechanical properties and composition of the Achilles tendon

Acromesomelic dysplasia of the Hunter–Thompson and Grebe types are rare human disorders based on growth/differentiation factor (GDF)-5/CDMP-1 genetic mutations. Numerous skeletal abnormalities are present in these individuals, including shortened limb bones and severe dislocations of the knee. In the GDF-5 deficient brachypodism mouse, similar, although less severe, phenotypes are observed. It is unknown whether the joint dislocations observed in these disorders are due to a defect in the original formation of joints such as the knee, or to abnormalities in the tendons and ligaments themselves. We hypothesized that tendons from GDF-5 deficient mice would exhibit altered composition, mechanical properties, and ultrastructure when compared with heterozygous control littermates. GDF-5 deficient Achilles tendons were structurally weaker than controls, and structural strength differences appeared to be caused by compromised material properties: after normalizing by collagen per unit length, mutant tendons were still 50% weaker ( P<0.0001) and 50% more compliant ( P<0.001) than controls. Despite comparable levels of skeletal maturity in the two cohorts, the majority of mutant tendon failures occurred in the mid-substance of the tendon (64% of all failures), whereas the majority of control failures occurred via avulsion (92% of all failures). Mutant Achilles tendons contained 40% less collagen per microgram of DNA when compared to controls ( P=0.004). No significant difference in glycosaminoglycan (GAG)/DNA was detected. Ultrastructural analyses indicated a slight trend toward increased frequency of small diameter (30–100 nm) collagen fibrils in the mutant Achilles. Our findings suggest that increased tendon and ligament laxity may be the cause of the joint dislocations seen in patients with Hunter–Thompson and Grebe type dysplasia, rather than developmental abnormalities in the joints themselves.

A novel member of the STOMATIN/EPB72/mec-2 family, stomatin-like 2 (STOML2), is ubiquitously expressed and localizes to HSA chromosome 9p13.1

A cDNA encoding a novel second member of the Band7/stomatin-like/SPFH domain family in humans designated stomatin-like 2 (STOML2) has been isolated using the technique of cDNA Representational Difference Analysis. The STOML2 cDNA encoded a 356 amino acid residue polypeptide with a predicted molecular weight of 38.5 kDa. The predicted polypeptide sequence of STOML2 could be delineated into three major domains: an N-terminal α-helical region; a domain with significant similarity to a 172 amino acid region of the HSA stomatin polypeptide, composed of an alternating α-helical and β-sheet structure and a C-terminal domain that was mostly α-helical. The stomatin-like domain was observed in 51 other proteins with potentially diverse functions. Based on its homology to stomatin, STOML2 was predicted to be cytoplasmically located. However, unlike most of the other proteins containing stomatin-like domains, the predicted STOML2 polypeptide does not contain a transmembrane region although the presence of N-myristoylation sites suggest that it has the potential to be membrane-associated. Northern blot analysis of a panel of poly(A)⁺ mRNA from normal human adult tissues showed that a single 1.3-kb mRNA transcript encoding STOML2 was ubiquitously expressed, with relatively higher levels in skeletal muscle and heart compared to other tissues. Comparison of the STOML2 cDNA sequence with human genomic DNA indicated that the gene encoding STOML2 was 3,250 bp long and consisted of ten exons interrupted by nine introns. We have mapped STOML2 to HSA chromosome 9p13.1, a region that is rearranged in some cancers and thought to contain the gene responsible for acromesomelic dysplasia.

Localization of an acromesomelic dysplasia on chromosome 9 by homozygosity mapping.

The acromesomelic dysplasias (AMDs) are a group of genetic disorders that primarily affect the middle and distal segments of the extremities. A form of AMD is present on the isolated island of St Helena in the South Atlantic, which has a population of approximately 5500 derived from a number of founder individuals. DNA from four affected individuals and 11 first-degree relatives in four related nuclear families segregating an AMD was collected for gene mapping studies. Six consecutive markers on chromosome 9, spanning an approximately 5 cM region, showed identical homozygosity in all affected individuals, thus identifying a region of homozygosity by descent. Multipoint analysis generated a maximum lod score of Z = 2.85. These data localize the gene for this dysplasia to the pericentromeric region of chromosome 9 where the gene for the Maroteaux form of AMD is situated. The identification of the gene responsible for this disorder may shed further light on the complex processes involved in limb morphogenesis.

Acromesomelic Dysplasia Maroteaux Type Maps to Human Chromosome 9

Acromesomelic dysplasias are skeletal disorders that disproportionately affect the middle and distal segments of the appendicular skeleton. We report genetic mapping studies in four families with acromesomelic dysplasia Maroteaux type (AMDM), an autosomal recessive osteochondrodysplasia. A peak LOD score of 5.1 at recombination fraction 0 was obtained with fully informative markers on human chromosome 9. In three of the four families, the affected offspring are products of consanguineous marriages; if it is assumed that these affected offspring are homozygous by descent for the region containing the AMDM locus, a 6.9-cM AMDM candidate interval can be defined by markers D9S1853 and D9S1874. The mapping of the AMDM locus to human chromosome 9 indicates that AMDM is genetically distinct from the two other mapped acromesomelic dysplasias, Hunter-Thompson type and Grebe type, which are caused by mutations in CDMP1 on human chromosome 20.

Grebe syndrome: Clinical and radiographic findings in affected individuals and heterozygous carriers

Grebe syndrome is a recessively inherited acromesomelic dysplasia. We studied, clinically and radiographically, 10 affected individuals, originating from Bahia, Brazil. The phenotype is characterized by a normal axial skeleton and severely shortened and deformed limbs, with a proximo-distal gradient of severity. The humeri and femora were relatively normal, the radii/ulnae and tibiae/fibulae were short and deformed, carpal and tarsal bones were fused, and several metacarpal and metatarsal bones were absent. The proximal and middle phalanges of the fingers and toes were invariably absent, while the distal phalanges were present. Postaxial polydactyly was found in several affected individuals. Several joints of the carpus, tarsus, hand, and foot were absent. Heterozygotes presented with a variety of skeletal manifestations including polydactyly, brachydactyly, hallux valgus, and metatarsus adductus. Grebe syndrome is caused by a missense mutation in the gene encoding cartilage-derived morphogenetic protein-1.

Ocular Findings in Acromesomelic Dysplasia

We examined an infant who had prenatal onset of a skeletal dysplasia that had many features in common with acromesomelic dysplasia, including the clinical and light and electron microscopic findings of both corneas. Successful lamellar keratoplasty was performed on the left eye when histologic examination of the corneal button from the right eye showed that the corneal scar was only of partial thickness.

An acromesomelic dysplasia with epi-metaphyseal involvement: a new entity

A unique acromesomelic epimetaphyseal dysplasia with presumed dominant inheritance has been observed in a 15-year-old male with normal stature.

Acromesomelic dysplasia of the maroteaux type

Acromesomelic dysplasia of the maroteaux type

Acromesomelic Dysplasia in a Father and Son: Autosomal Dominant Inheritance

A father and son with typical acromesomelic dysplasia are reported, with the father more severely affected than the son. The disease was thus apparently transmitted in an autosomal dominant fashion. This is at variance with the autosomal recessive mode of inheritance assumed from hitherto reported families.

Diagnostic test for mucopolysaccharidosis. II. Rapid quantification of glycosaminoglycan in urine samples collected on a paper matrix.

The direct 1,9-dimethylmethylene blue (DMB) method for quantifying sulfated glycosaminoglycan (GAG) in urine (Clin Chem 1989; 35:374-9) has been adapted to a convenient means for sample collection and transport as a test to identify individuals with mucopolysaccharidosis (MPS) storage diseases. Results correlated moderately well (r = 0.85) with those of a commonly used, but more laborious, quantitative method. In studying factors to maximize differentiation of pathological from normal values, we found that GAG excretion (expressed as milligrams GAG per gram creatinine) fits a logarithmic function with respect to age and varies markedly below age five years. This must be considered in developing normative values and forming diagnoses. Of 112 separate urine specimens obtained from 41 MPS patients representing the major MPS diseases, glycosaminoglycan excretion by all exceeded that for age-matched normal individuals. The convenience of this method allowed us to establish the first normative values for three-week-old infants (n = 435) found to have a mean glycosaminoglycan excretion of 179 (SD 86.3) mg of GAG per gram of creatinine. This method improves the diagnostic capability for those MPS diseases that have been particularly difficult to identify (Sanfilippo's syndrome and Morquio's syndrome), and may also provide a test for other disorders with previously unrecognized abnormal excretion of glycosaminoglycan (e.g., mucolipidosis and acromesomelic dysplasia). Most importantly, this MPS diagnostic test is unique in its suitability for mass screening of newborn infants.

Acromesomelic dysplasia: Radiologic, clinical, and pathological study

We report a 51-year-old woman with acromesomelic dysplasia. Pathologic studies on adult bone are reported. Hydrocephalus and mild oligophrenia are additional findings.

A case of chondrodystrophic dwarfism in the Italian late Upper Paleolithic.

During excavations by P. Graziosi at Romito Cave near Papasidero (Cosenza) in Calabria, Italy, two skeletons (Romito 1 and 2) were discovered in a common grave. Although the specimens were briefly described by Messeri (Atti X Riuniuone Scientifica Ist. Ital. Preist. Protost., pp. 301-307, 1966), it is generally unknown in the anthropological literature that one of these individuals is a chondrodystrophic dwarf. As such, the specimen provides the earliest known case of dwarfism in the human skeletal record, extending the time span of this genetically determined growth abnormality to approximately 10,000 years ago. The specimen (Romito 2) exhibits features typical of chondrodysplasia, including a high domed skull, compressed cranial base, and in the postcranial skeleton extremely shortened diaphyseal lengths. The unique combination of these features suggests this pathological condition is acromesomelic dysplasia. Besides providing evidence for a greater antiquity of dwarfism than previously known, the fact that this individual reached late adolescence attests to tolerance of Upper Paleolithic groups for severely abnormal individuals and their ability to support members who were of limited economic value to the social group.

Dwarfism in an adolescent from the Italian late Upper Palaeolithic.

There have been numerous reports of pathological conditions in the hominid fossils, but these have only involved trauma or age-related deterioration in the health of otherwise normal individuals. Here we describe a skeleton of a young male from Riparo del Romito in Calabria, dated to the Epi-Gravettian of southern Italy. The preserved skeletal elements show that this individual (Romito 2) had the skull and long-bone morphology consistent with a mesomelic form of dwarfism, most probably the autosomal recessive disorder acromesomelic dysplasia. Generally recognized at birth, persons with acromesomelic dysplasia usually have normal intelligence and are free of serious medical problems. However, growth deficiency is severe (adult height typically is 110-120 cm) and mobility at the elbows is restricted. These physical impairments would have greatly interfered with the individual's participation in subsistence activities and would have been a substantial handicap in a nomadic hunting and gathering group. Thus, besides being the earliest known case of dwarfism in the human record, this skeleton provides evidence of tolerance of, and care for, a severely deformed individual in the Palaeolithic.

1206 ACROMESOMELIC DYSPLASIA, A HISTOCHEMICAL STUDY OF THE ENDOCHONRAL GROWTH PLATE

Endochondral growth plate cartilage from a patient with the typical clinical and radiographic features of acromesomelic dysplasia was studied histochemically and immunohistochemically. The investigation revealed many previously undescribed abnormalities. The cartilage was hypercellular in general. There were numerous small areas of matrix degeneration scattered through the resting zone and a few large islands of hypertrophic cartilage in the growth plate region. Staining indicated excessive amounts of chondroitin sulfate and an absence of collagen fibers in both of these areas. In the remaining cartilage, collagen fibers tended to aggregate around the cells. The resting chondrocytes were irregular in size and distribution, and many exhibited protein containing cytoplasmic inclusions. The growth plate per se was poorly organized; hypertrophic chondrocytes were randomly oriented. The provisional calcification of cartilage matrix was absent, but the mineralization of subchondral bone appeared normal except along the outer margin where bone formation extended into the perichondrial space. These abnormalities appear to be distinct for acromesomelic dysplasia. Moreover, they provide several clues regarding the pathogenesis of the disorder.

Acromesomelic dysplasia.

The radiographic features of acromesomelic dysplasia are presented, along with a summary of pertinent clinical features. They are thought to allow a diagnosis in affected individuals over six months of age. Since the condition has an autosomal recessive mode of genetic transmission and results in extremely short stature, the establishment of the diagnosis has practical importance.