Distinctive new form of spondyloepimetaphyseal dysplasia with severe metaphyseal changes similar to Jansen metaphyseal chondrodysplasia

Kaissi, Ali Al; Ghachem, MB; Nessib, Nebil; Chehida, FB; Hammou, A.; Kozlowski, K.

doi:10.1111/j.1440-1673.2005.01395.x

Cited by 3 publications

(3 citation statements)

References 13 publications

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“…Interestingly, we could confirm the previously reported decrease in collagen type X expression in the Col2Cre-Zfp521 growth plate (12). 8,26). Macroscopic appearance and bone length of all four genotypes.…”

Section: Col2cre Col2cresupporting

confidence: 90%

“…One of the hallmark phenotypes in Jansen metaphyseal chondrodysplasia is markedly retarded ossification in endochondral bones, i.e., cervical and lumbar vertebrae (radiography detected at 12 mo in patient, distorted ossification; refs. 8,26). Here, we also found that chondrocyte differentiation was improved in newborn sternebrae of double mutants, as indicated by the accelerated chondrocyte differentiation and the appearance of a secondary ossification center in the tibia.…”

Section: Col2cre Col2cresupporting

confidence: 66%

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Deletion of Zfp521 rescues the growth plate phenotype in a mouse model of Jansen metaphyseal chondrodysplasia

et al. 2011

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Jansen metaphyseal chondrodysplasia (JMC) is caused by a constitutively activating mutation of the parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptor (PTHR1) and is characterized by widening of the metaphyses, reduction of long bone length, and short stature. A transgenic mouse expressing this mutation under the collagen α1(II) promoter has been generated to investigate the mechanisms responsible for this chondrodysplasia. We recently identified zinc finger protein 521 (Zfp521) as a downstream target gene of PTHrP signaling. Interestingly, loss of Zfp521 from chondrocytes leads to reduced cell proliferation and increased differentiation in the growth plate. Thus, we hypothesized that specifically ablating Zfp521 from Jansen chondrocytes could sufficiently rescue the chondrodysplasia phenotype. Our results show that Zfp521 expression is up-regulated in Jansen mouse growth plate chondrocytes and that PTHR1 is required for Zfp521 expression. Its ablation from Jansen chondrocytes restored normal cell differentiation, thus initiating chondrocyte apoptosis at the chondro-osseous junction, leading to partial rescue of endochondral bone formation shown by proper bone length. This study provides the first genetic evidence that Zfp521 is required downstream of PTHR1 signaling to act on chondrocyte proliferation, differentiation, and cell death.

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Section: Col2cre Col2cresupporting

confidence: 90%

Section: Col2cre Col2cresupporting

confidence: 66%

Deletion of Zfp521 rescues the growth plate phenotype in a mouse model of Jansen metaphyseal chondrodysplasia

et al. 2011

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“…Addressing whether the identified family represents an isolated finding, review of the literature revealed a report of a 1-year-old male from a consanguineous mating with similar radiographic and clinical findings to our patients, particularly the findings of the frontal bossing, hypertelorism, prominent joints, psychomotor delay, hypercalcemia, a transverse gap in the ulna and marked epiphyseal delay with absent ossification of the pubis, and a highly irregularly distorted metaphyses (31). JMC was considered in that report but was excluded as final diagnosis based on the unique constellation of findings.…”

Section: Discussionmentioning

confidence: 53%

The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling

et al. 2018

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Studies have suggested a role for the mammalian (or mechanistic) target of rapamycin (mTOR) in skeletal development and homeostasis, yet there is no evidence connecting mTOR with the key signaling pathways that regulate skeletogenesis. We identified a parathyroid hormone (PTH)/PTH-related peptide (PTHrP)-salt-inducible kinase 3 (SIK3)-mTOR signaling cascade essential for skeletogenesis. While investigating a new skeletal dysplasia caused by a homozygous mutation in the catalytic domain of SIK3, we observed decreased activity of mTOR complex 1 (mTORC1) and mTORC2 due to accumulation of DEPTOR, a negative regulator of both mTOR complexes. This SIK3 syndrome shared skeletal features with Jansen metaphyseal chondrodysplasia (JMC), a disorder caused by constitutive activation of the PTH/PTHrP receptor. JMC-derived chondrocytes showed reduced SIK3 activity, elevated DEPTOR, and decreased mTORC1 and mTORC2 activity, indicating a common mechanism of disease. The data demonstrate that SIK3 is an essential positive regulator of mTOR signaling that functions by triggering DEPTOR degradation in response to PTH/PTHrP signaling during skeletogenesis.

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Genetic diseases in the Tunisian population

Romdhane

Abdelhak

2010

American J of Med Genetics Pt A

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Tunisia is one of the North African countries, geographically situated in a central position at the crossroad between Africa and Europe. The demographic features of the Tunisian population include among others high rates of consanguinity. We report, here on the spectrum of genetic diseases in Tunisia. The review of the literature, including other available information (gray literature) showed that there are at least 346 genetic disorders for which cases have been identified in the Tunisian population. Among these, 62.9% are autosomal recessive, 23% autosomal dominant, 5.4% X-linked, and the remaining are of Y-linked, mitochondrial, and unknown mode of transmission. Fifty percent of the reported conditions in this study are caused by at least one mutation. For autosomal recessive diseases, most of the mutations were identified at homozygous state among the affected individuals. Part of the mutations was the result of a founder effect; these are the consequences of the high rate of consanguinity. The congenital malformations, diseases of the nervous system and metabolic disorders are the major groups of genetic diseases affecting the Tunisian population. The large spectrum of diseases and their relatively high frequency could be explained by the high degree of inbreeding and the presence of multiple mutations, either allelic or in different genes. This is due to the richness of the genetic background of the studied population. A multidisciplinary approach is essential to develop adequate preventive programmes adapted to the social, cultural, and economic context.

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Distinctive new form of spondyloepimetaphyseal dysplasia with severe metaphyseal changes similar to Jansen metaphyseal chondrodysplasia

Cited by 3 publications

References 13 publications

Deletion of Zfp521 rescues the growth plate phenotype in a mouse model of Jansen metaphyseal chondrodysplasia

Deletion of Zfp521 rescues the growth plate phenotype in a mouse model of Jansen metaphyseal chondrodysplasia

The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling

Genetic diseases in the Tunisian population

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