Achondrogenesis Type IA (Houston-Harris): A Still-Unresolved Molecular Phenotype

Aigner, Thomas; Rau, Tilman T.; Niederhagen, Manuel; Zaucke, Frank; Pöhls, Uwe; Stöss, Helmut; Rauch, Anita; Thiel, Christian T.

doi:10.2350/06-07-0134.1

Cited by 9 publications

(13 citation statements)

References 20 publications

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“…The absence of vertebral-body and skull ossification on radiography, the lack of organized columnar zones of proliferating chondrocytes on histologic analysis, the reduced expression of Col10a1 on immunohistochemical analysis, and the expanded endoplasmic reticulum cisternae in chondrocytes on electron microscopy have all been reported in affected patients. 3,11 We performed sequence analysis of TRIP11 in our 10 unrelated patients with achondrogenesis type 1A and found loss-of-function mutations in each patient (Fig. 5B).…”

Section: Resultsmentioning

confidence: 99%

Lethal Skeletal Dysplasia in Mice and Humans Lacking the Golgin GMAP-210

et al. 2010

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BACKGROUND Establishing the genetic basis of phenotypes such as skeletal dysplasia in model organisms can provide insights into biologic processes and their role in human disease. METHODS We screened mutagenized mice and observed a neonatal lethal skeletal dysplasia with an autosomal recessive pattern of inheritance. Through genetic mapping and positional cloning, we identified the causative mutation. RESULTS Affected mice had a nonsense mutation in the thyroid hormone receptor interactor 11 gene (Trip11), which encodes the Golgi microtubule-associated protein 210 (GMAP-210); the affected mice lacked this protein. Golgi architecture was disturbed in multiple tissues, including cartilage. Skeletal development was severely impaired, with chondrocytes showing swelling and stress in the endoplasmic reticulum, abnormal cellular differentiation, and increased cell death. Golgi-mediated glycosylation events were altered in fibroblasts and chondrocytes lacking GMAP-210, and these chondrocytes had intracellular accumulation of perlecan, an extracellular matrix protein, but not of type II collagen or aggrecan, two other extracellular matrix proteins. The similarities between the skeletal and cellular phenotypes in these mice and those in patients with achondrogenesis type 1A, a neonatal lethal form of skeletal dysplasia in humans, suggested that achondrogenesis type 1A may be caused by GMAP-210 deficiency. Sequence analysis revealed loss-of-function mutations in the 10 unrelated patients with achondrogenesis type 1A whom we studied. CONCLUSIONS GMAP-210 is required for the efficient glycosylation and cellular transport of multiple proteins. The identification of a mutation affecting GMAP-210 in mice, and then in humans, as the cause of a lethal skeletal dysplasia underscores the value of screening for abnormal phenotypes in model organisms and identifying the causative mutations.

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Section: Resultsmentioning

confidence: 99%

Lethal Skeletal Dysplasia in Mice and Humans Lacking the Golgin GMAP-210

et al. 2010

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“…Some studies have reported a short neck, protruding eyes, flat nasal bridge, and low-set ears. 1 , 2 Affected individuals die in utero or shortly after birth. Radiological findings show short-cupped flared ribs, deficient ossification in the skull, lumbar vertebrae, extremities, and sacral and ischial bones.…”

Section: Introductionmentioning

confidence: 99%

“… 4 Genetic and experimental analysis has shown that ACG1A is caused by a mutation in the thyroid hormone receptor interactor 11 gene ( TRIP11 ) encoding Golgi microtubule-binding protein 210 (GMAP-210) required for efficient glycosylation and cellular transport of multiple proteins. 2 Other TRIP11 mutations could lead to abnormal skin, altered chondrogenesis, and lethal skeletal dysplasias. 2 , 4 …”

Section: Introductionmentioning

confidence: 99%

Achondrogenesis type 1A: clinical, histologic, molecular, and prenatal ultrasound diagnosis

Vanegas

Sua

López-Tenorio

et al. 2018

TACG

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BackgroundAchondrogenesis 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 TRIP11, which encodes Golgi microtubule-binding protein 210 in the Golgi apparatus, alter protein transport in tissues.Case presentationA 28-week gestation male fetus was diagnosed with ACG1A by clinical, radiological, histologic, and molecular findings.ResultsWhole exome sequencing was performed on fetal DNA and parental blood. Two fetal heterozygous novel variants of TRIP11, 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.ConclusionTo 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.

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“…Differentiation between types IA and IB is more problematic. Abnormal staining and ultrastructural properties of the matrix around chondrocytes has been reported as specific to type IB, an observation supported by the case report of Aigner and colleagues [1] However, a comparison between SLC26A2 mutational analysis and histochemical staining for a large series of type IA and IB patients to determine the sensitivity and specificity of the histochemical approach has yet to be reported. Therefore, SLC26A2 sequencing may be useful to differentiate between types IA and IB, particularly if histologic studies are not available.…”

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confidence: 79%

“…With the possible unusual exception of in vitro fertilization and embryo selection based on preimplantation diagnosis, prenatal molecular diagnosis has a limited role in cases of achondrogenesis, because the phenotype is invariably severe and can be detected sonographically early in gestation. Hence, studies like that of Aigner and colleagues [1], which identify distinctive phenotypic features of achondrogenesis variants and, better yet, compare their sensitivity and specificity with molecular diagnostic techniques, may reduce unnecessary and expensive molecular tests.…”

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confidence: 99%