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The Application of Clinical Genetics 2018Achondrogenesis type IA (ACG1A) is a rare, lethal autosomal recessive chondrodysplasia affecting endochondral bone ossification and differentiation, causing intrauterine...
BACKGROUND
Achondrogenesis type IA (ACG1A) is a rare, lethal autosomal recessive chondrodysplasia affecting endochondral bone ossification and differentiation, causing intrauterine growth restriction, narrow thorax, and short limbs. Mutations in , which encodes Golgi microtubule-binding protein 210 in the Golgi apparatus, alter protein transport in tissues.
CASE PRESENTATION
A 28-week gestation male fetus was diagnosed with ACG1A by clinical, radiological, histologic, and molecular findings.
RESULTS
Whole exome sequencing was performed on fetal DNA and parental blood. Two fetal heterozygous novel variants of , c.2304_2307delTCAA (p.Asn768Lysfs*7) and c.2128_2129delAT (p.lle710Cysfs*19), were inherited from the mother and father, respectively. Both variants created a reading frameshift leading to a premature stop codon and loss of protein function.
CONCLUSION
To our knowledge, this is the first Latin American report with clinical, radiographic, and molecular diagnosis of ACG1A. Clinical and molecular diagnosis in utero is essential for genotype-phenotype correlation and is useful for providing better genetic counseling.
PubMed: 29872333
DOI: 10.2147/TACG.S157235 -
Human Genome Variation Nov 2022Achondrogenesis type II (ACG2) is a lethal skeletal disorder caused by pathogenic variants in COL2A1. We present a fetus with cystic hygroma and severe shortening of the...
Achondrogenesis type II (ACG2) is a lethal skeletal disorder caused by pathogenic variants in COL2A1. We present a fetus with cystic hygroma and severe shortening of the limbs at 14 weeks of gestation. We performed postnatal genetic analysis of the parents and fetus to diagnose the disease. A novel missense variant of COL2A1 [NM_001844.5: c.2987G>A, (p. Gly996Asp)] was identified, which led to the ACG2 diagnosis.
PubMed: 36376277
DOI: 10.1038/s41439-022-00218-5 -
EBioMedicine Feb 2019Mutations in the SLC26A2 gene cause a spectrum of currently incurable human chondrodysplasias. However, genotype-phenotype relationships of SLC26A2-deficient...
BACKGROUND
Mutations in the SLC26A2 gene cause a spectrum of currently incurable human chondrodysplasias. However, genotype-phenotype relationships of SLC26A2-deficient chondrodysplasias are still perplexing and thus stunt therapeutic development.
METHODS
To investigate the causative role of SLC26A2 deficiency in chondrodysplasias and confirm its skeleton-specific pathology, we generated and analyzed slc26a2 and Col2a1-Cre; slc26a2 mice. The therapeutic effect of NVP-BGJ398, an FGFR inhibitor, was tested with both explant cultures and timed pregnant females.
FINDINGS
Two lethal forms of human SLC26A2-related chondrodysplasias, achondrogenesis type IB (ACG1B) and atelosteogenesis type II (AO2), are phenocopied by slc26a2 mice. Unexpectedly, slc26a2 chondrocytes are defective for collagen secretion, exhibiting intracellular retention and compromised extracellular deposition of ColII and ColIX. As a consequence, the ATF6 arm of the unfolded protein response (UPR) is preferentially triggered to overactivate FGFR3 signaling by inducing excessive FGFR3 in slc26a2 chondrocytes. Consistently, suppressing FGFR3 signaling by blocking either FGFR3 or phosphorylation of the downstream effector favors the recovery of slc26a2 cartilage cultures from impaired growth and unbalanced cell proliferation and apoptosis. Moreover, administration of an FGFR inhibitor to pregnant females shows therapeutic effects on pathological features in slc26a2 newborns. Finally, we confirm the skeleton-specific lethality and pathology of global SLC26A2 deletion through analyzing the Col2a1-Cre; slc26a2 mouse line.
INTERPRETATION
Our study unveils a previously unrecognized pathogenic mechanism underlying ACG1B and AO2, and supports suppression of FGFR3 signaling as a promising therapeutic approach for SLC26A2-related chondrodysplasias. FUND: This work was supported by National Natural Science Foundation of China (81871743, 81730065 and 81772377).
Topics: Achondroplasia; Activating Transcription Factor 6; Animals; Cartilage; Cell Differentiation; Chondrocytes; Disease Models, Animal; Disease Susceptibility; Gene Expression Regulation, Developmental; Growth Plate; Humans; Mice; Mice, Knockout; Morphogenesis; Mutation; Osteochondrodysplasias; Phenotype; Receptor, Fibroblast Growth Factor, Type 3; Signal Transduction; Sulfate Transporters; Unfolded Protein Response
PubMed: 30685387
DOI: 10.1016/j.ebiom.2019.01.010 -
Development (Cambridge, England) Jan 2018Inactivating mutations in the ubiquitously expressed membrane trafficking component GMAP-210 (encoded by ) cause achondrogenesis type 1A (ACG1A). ACG1A is surprisingly...
Inactivating mutations in the ubiquitously expressed membrane trafficking component GMAP-210 (encoded by ) cause achondrogenesis type 1A (ACG1A). ACG1A is surprisingly tissue specific, mainly affecting cartilage development. Bone development is also abnormal, but as chondrogenesis and osteogenesis are closely coupled, this could be a secondary consequence of the cartilage defect. A possible explanation for the tissue specificity of ACG1A is that cartilage and bone are highly secretory tissues with a high use of the membrane trafficking machinery. The perinatal lethality of ACG1A prevents investigating this hypothesis. We therefore generated mice with conditional knockout alleles and inactivated in chondrocytes, osteoblasts, osteoclasts and pancreas acinar cells, all highly secretory cell types. We discovered that the ACG1A skeletal phenotype is solely due to absence of GMAP-210 in chondrocytes. Mice lacking GMAP-210 in osteoblasts, osteoclasts and acinar cells were normal. When we inactivated in primary chondrocyte cultures, GMAP-210 deficiency affected trafficking of a subset of chondrocyte-expressed proteins rather than globally impairing membrane trafficking. Thus, GMAP-210 is essential for trafficking specific cargoes in chondrocytes but is dispensable in other highly secretory cells.
Topics: Achondroplasia; Alleles; Animals; Biological Transport, Active; Bone Development; Cartilage; Chondrocytes; Cytoskeletal Proteins; Mice; Mice, Knockout; Nuclear Proteins; Osteoblasts; Osteoclasts; Phenotype
PubMed: 29180569
DOI: 10.1242/dev.156588 -
PloS One 2017Most types of crime are known to exhibit seasonal oscillations, yet the annual variations in the amplitude of this seasonality and their causes are still uncertain....
Most types of crime are known to exhibit seasonal oscillations, yet the annual variations in the amplitude of this seasonality and their causes are still uncertain. Using a large collection of data from the Houston and Los Angeles Metropolitan areas, we extract and study the seasonal variations in aggravated assault, break in and theft from vehicles, burglary, grand theft auto, rape, robbery, theft, and vandalism for many years from the raw daily data. Our approach allows us to see various long term and seasonal trends and aberrations in crime rates that have not been reported before. We then apply an ecologically motivated stochastic differential equation to reproduce the data. Our model relies only on social interaction terms, and not on any exigent factors, to reproduce both the seasonality, and the seasonal aberrations observed in our data set. Furthermore, the stochasticity in the system is sufficient to reproduce the variations seen in the seasonal oscillations from year to year. Researchers should be very careful about trying to correlate these oscillations with external factors.
Topics: Achondroplasia; Crime; Humans; Los Angeles; Models, Theoretical; Seasons; Social Behavior; Temperature; Time Factors
PubMed: 28938022
DOI: 10.1371/journal.pone.0185432 -
American Journal of Human Genetics Dec 1988We have extended the study of a mild case of type II achondrogenesis-hypochondrogenesis to include biochemical analyses of cartilage, bone, and the collagens produced by...
We have extended the study of a mild case of type II achondrogenesis-hypochondrogenesis to include biochemical analyses of cartilage, bone, and the collagens produced by dermal fibroblasts. Type I collagen extracted from bone and types I and III collagen produced by dermal fibroblasts were normal, as was the hexosamine ratio of cartilage proteoglycans. Hyaline cartilage, however, contained approximately equal amounts of types I and II collagen and decreased amounts of type XI collagen. Unlike the normal SDS-PAGE mobility. Two-dimensional SDS-PAGE revealed extensive overmodification of all type II cyanogen bromide peptides in a pattern consistent with heterozygosity for an abnormal pro alpha 1(II) chain which impaired the assembly and/or folding of type II collagen. This interpretation implies that dominant mutations of the COL2A1 gene may cause type II achondrogenesis-hypochondrogenesis. More generally, emerging data implicating defects of type II collagen in the type II achondrogenesis-hypochondrogenesis-spondyloepiphyseal dysplasia congenita spectrum and in the Kniest-Stickler syndrome spectrum suggest that diverse mutations of this gene may be associated with widely differing phenotypic outcome.
Topics: Amino Acids; Bone and Bones; Cartilage; Collagen; Electrophoresis, Gel, Two-Dimensional; Female; Hexosamines; Humans; Infant, Newborn; Osteochondrodysplasias; Protein Conformation
PubMed: 3195588
DOI: No ID Found -
JCI Insight Dec 2018Biallelic loss-of-function mutations in TRIP11, encoding the golgin GMAP-210, cause the lethal human chondrodysplasia achondrogenesis 1A (ACG1A). We now find that a...
Biallelic loss-of-function mutations in TRIP11, encoding the golgin GMAP-210, cause the lethal human chondrodysplasia achondrogenesis 1A (ACG1A). We now find that a homozygous splice-site mutation of the lamin B receptor (LBR) gene results in the same phenotype. Intrigued by the genetic heterogeneity, we compared GMAP-210- and LBR-deficient primary cells to unravel how particular mutations in LBR cause a phenocopy of ACG1A. We could exclude a regulatory interaction between LBR and GMAP-210 in patients' cells. However, we discovered a common disruption of Golgi apparatus architecture that was accompanied by decreased secretory trafficking in both cases. Deficiency of Golgi-dependent glycan processing indicated a similar downstream effect of the disease-causing mutations upon Golgi function. Unexpectedly, our results thus point to a common pathogenic mechanism in GMAP-210- and LBR-related diseases attributable to defective secretory trafficking at the Golgi apparatus.
Topics: Achondroplasia; Biological Transport, Active; Cell Proliferation; Cell Survival; Cholesterol; Cytoskeletal Proteins; Endoplasmic Reticulum; Female; Fetus; Fibroblasts; Genetic Diseases, Inborn; Golgi Apparatus; Humans; Mutation; Nuclear Proteins; Pedigree; Phenotype; Receptors, Cytoplasmic and Nuclear; Sequence Analysis, Protein; Sterols; Transcription Factors; Lamin B Receptor
PubMed: 30518689
DOI: 10.1172/jci.insight.121150 -
Journal of Anatomy Dec 1990Knowledge of the structure of cartilage vascular canals is important for a more thorough understanding of the development of cartilage and the growth plate in the human... (Comparative Study)
Comparative Study
Knowledge of the structure of cartilage vascular canals is important for a more thorough understanding of the development of cartilage and the growth plate in the human neonate and growing child. We have studied the costochondral junction of 6 normal neonates and 12 normal children (age 4 months-16 years) and utilised quantitative histomorphometry to define the percentage tissue area occupied by canals and the number of canals/mm2. Both percentage canal area and the number of canals/mm2 were significantly greater in newborn vs. older children (percentage area: 0.42 +/- 0.15 (mean +/- S.E.M.) vs. 0.08 +/- 0.04, P = 0.003; number/mm2: 0.2 +/- 0.09 vs. 0.04 +/- 0.02, P = 0.02). Eight newborn patients with achondrogenesis II-hypochondrogenesis were also studied. Both percentage canal area and number were significantly elevated above normal (percentage area: 5.22 +/- 1.01, P less than 0.001; number/mm2: 1.45 +/- 0.26, P less than 0.001). Results presented here demonstrate that: (i) quantitative differences in vascular canal area and numbers occur during development; (ii) 10-fold increases in vascular canal area and number are present in achondrogenesis II-hypochondrogenesis. Data from normal subjects will provide normative values against which vascular abnormalities in other skeletal dysplasias can be compared.
Topics: Aging; Cartilage; Child; Child, Preschool; Humans; Infant, Newborn; Infant, Newborn, Diseases; Osteochondrodysplasias; Regional Blood Flow; Ribs
PubMed: 2074231
DOI: No ID Found -
Development (Cambridge, England) Nov 2020The Hippo-YAP/TAZ pathway is an important regulator of tissue growth, but can also control cell fate or tissue morphogenesis. Here, we investigate the function of the...
The Hippo-YAP/TAZ pathway is an important regulator of tissue growth, but can also control cell fate or tissue morphogenesis. Here, we investigate the function of the Hippo pathway during the development of cartilage, which forms the majority of the skeleton. Previously, YAP was proposed to inhibit skeletal size by repressing chondrocyte proliferation and differentiation. We find that, , / double knockout impairs murine chondrocyte proliferation, whereas constitutively nuclear accelerates proliferation, in line with the canonical role of this pathway in most tissues. However, , cartilage-specific knockout of / does not prevent chondrocyte proliferation, differentiation or skeletal growth, but rather results in various skeletal deformities including cleft palate. Cartilage-specific expression of or knockout of / do not increase cartilage growth, but instead lead to catastrophic malformations resembling chondrodysplasia or achondrogenesis. Physiological YAP target genes in cartilage include , and several matrix remodelling enzymes. Thus, YAP/TAZ activity controls chondrocyte proliferation , possibly reflecting a regenerative response, but is dispensable for chondrocyte proliferation , and instead functions to control cartilage morphogenesis via regulation of the extracellular matrix.
Topics: Adaptor Proteins, Signal Transducing; Animals; Bone and Bones; Cartilage; Cell Cycle Proteins; Cell Nucleus; Cell Proliferation; Chondrocytes; Cleft Palate; Extracellular Matrix; Gene Expression Regulation, Developmental; Growth Plate; Hippo Signaling Pathway; Mice; Mice, Inbred C57BL; Mice, Knockout; Morphogenesis; Protein Serine-Threonine Kinases; Signal Transduction; Trans-Activators; Tumor Suppressor Proteins; YAP-Signaling Proteins
PubMed: 32994166
DOI: 10.1242/dev.187187 -
Archives of Disease in Childhood Mar 1977
Topics: Achondroplasia; Humans; Infant
PubMed: 849009
DOI: 10.1136/adc.52.3.253