New gene discoveries in skeletal diseases with short stature

Costantini, Alice; Muurinen, Mari; Mäkitie, Outi

doi:10.1530/ec-21-0083

Cited by 9 publications

(7 citation statements)

References 109 publications

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“… 22 – 26 Serial wrist radiographs obtained during healthy adolescence showed distal radius rates of periosteal resorption and endocortical apposition averaged 8 μm·d −1 and 10 μm·d −1 , respectively. 27 Although human short stature can result from disruptions in at least 60 genes influencing longitudinal bone growth, 28 bone lengths are unaffected in Pyle´s disease subjects and Sfrp4 KO mice. Therefore, SFRP4 does not appear to influence formation and maintenance of articular cartilage and epiphyseal bone, nor growth plate dynamics.…”

Section: Discussionmentioning

confidence: 99%

Skeletal phenotypes in secreted frizzled-related protein 4 gene knockout mice mimic skeletal architectural abnormalities in subjects with Pyle’s disease from SFRP4 mutations

2023

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Mutations in SFRP4 cause Pyle’s bone disease with wide metaphyses and increased skeletal fragility. The WNT signaling pathway plays important roles in determining skeletal architecture and SFRP4 is a secreted Frizzled decoy receptor that inhibits WNT signaling. Seven cohorts of male and female Sfrp4 gene knockout mice, examined through 2 years of age, had a normal lifespan but showed cortical and trabecular bone phenotypes. Mimicking human Erlenmeyer flask deformities, bone cross-sectional areas were elevated 2-fold in the distal femur and proximal tibia but only 30% in femur and tibia shafts. Reduced cortical bone thickness was observed in the vertebral body, midshaft femur and distal tibia. Elevated trabecular bone mass and numbers were observed in the vertebral body, distal femur metaphysis and proximal tibia metaphysis. Midshaft femurs retained extensive trabecular bone through 2 years of age. Vertebral bodies had increased compressive strength, but femur shafts had reduced bending strength. Trabecular, but not cortical, bone parameters in heterozygous Sfrp4 mice were modestly affected. Ovariectomy resulted in similar declines in both cortical and trabecular bone mass in wild-type and Sfrp4 KO mice. SFRP4 is critical for metaphyseal bone modeling involved in determining bone width. Sfrp4 KO mice show similar skeletal architecture and bone fragility deficits observed in patients with Pyle’s disease with SFRP4 mutations.

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Section: Discussionmentioning

confidence: 99%

Skeletal phenotypes in secreted frizzled-related protein 4 gene knockout mice mimic skeletal architectural abnormalities in subjects with Pyle’s disease from SFRP4 mutations

2023

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“…Skeletal dysplasias are characterized by broad phenotypic and genetic heterogeneity. Clinically, the phenotype can vary greatly among patients with the same gene defect and significantly even among those harboring the exact same pathogenic variant (Costantini et al, 2021). The clinical differentiation between SEMD types is extremely difficult and complex.…”

Section: Discussionmentioning

confidence: 99%

A novel variant in GNPNAT1 gene causing a spondylo‐epi‐metaphyseal dysplasia resembling PGM3—Desbuquois like dysplasia

Elhossini

Ahmed

Otaify

et al. 2022

American J of Med Genetics Pt A

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Spondylo-epi-metaphyseal dysplasias (SEMDs) are a clinically and genetically heterogeneous group of skeletal dysplasias characterized by short stature and abnormal modeling of the spine and long bones. A novel form of rhizomelic skeletal dysplasia, Ain-Naz type, associated with a homozygous variant in GNPNAT1 was recently identified. Herein, we report an Egyptian patient, offspring of consanguineous parents, who presented with a severe form of unclassified SEMD. Whole exome sequencing identified a novel homozygous variant in exon 3, c.77T>G, (p.Phe26Cys) in GNPNAT1, that was confirmed by Sanger sequencing and both parents were found to be heterozygous for the identified variant. Main features included severe short stature, rhizomelic limb shortening, and wide flared metaphysis. Short broad long bones, brachydactyly, delayed epiphyseal ossification of long bones, advanced bone age, and immunodeficiency were additional findings expanding the clinical phenotype described in the previously reported family. We conclude that variants in the GNPNAT1 gene cause an autosomal recessive form of SEMD resembling Desbuquois like dysplasia caused by PGM3, which is involved in the same pathway as GNPNAT1.

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“…The greatest obstacle, however, lies with delivery and the inability to transduce enough cells in tissues of human-scale to mediate a meaningful effect ( Dai et al, 2016 ). This is especially problematic in orthopaedics ( Fitzgerald, 2020 ), where the target tissues are ECM-dense and the predominant monogenic disorders are skeletal dysplasias (e.g., achondroplasia and osteogenesis imperfecta) that generate abnormalities throughout the entire skeletal system ( Krakow and Rimoin, 2010 ; Costantini et al, 2021 ).…”

Section: Gene Editing- Crispr/cas9mentioning

confidence: 99%

Gene Therapy in Orthopaedics: Progress and Challenges in Pre-Clinical Development and Translation

Watson-Levings

Palmer

Levings

et al. 2022

Front. Bioeng. Biotechnol.

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In orthopaedics, gene-based treatment approaches are being investigated for an array of common -yet medically challenging- pathologic conditions of the skeletal connective tissues and structures (bone, cartilage, ligament, tendon, joints, intervertebral discs etc.). As the skeletal system protects the vital organs and provides weight-bearing structural support, the various tissues are principally composed of dense extracellular matrix (ECM), often with minimal cellularity and vasculature. Due to their functional roles, composition, and distribution throughout the body the skeletal tissues are prone to traumatic injury, and/or structural failure from chronic inflammation and matrix degradation. Due to a mixture of environment and endogenous factors repair processes are often slow and fail to restore the native quality of the ECM and its function. In other cases, large-scale lesions from severe trauma or tumor surgery, exceed the body’s healing and regenerative capacity. Although a wide range of exogenous gene products (proteins and RNAs) have the potential to enhance tissue repair/regeneration and inhibit degenerative disease their clinical use is hindered by the absence of practical methods for safe, effective delivery. Cumulatively, a large body of evidence demonstrates the capacity to transfer coding sequences for biologic agents to cells in the skeletal tissues to achieve prolonged delivery at functional levels to augment local repair or inhibit pathologic processes. With an eye toward clinical translation, we discuss the research progress in the primary injury and disease targets in orthopaedic gene therapy. Technical considerations important to the exploration and pre-clinical development are presented, with an emphasis on vector technologies and delivery strategies whose capacity to generate and sustain functional transgene expression in vivo is well-established.

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New gene discoveries in skeletal diseases with short stature

Cited by 9 publications

References 109 publications

Skeletal phenotypes in secreted frizzled-related protein 4 gene knockout mice mimic skeletal architectural abnormalities in subjects with Pyle’s disease from SFRP4 mutations

Skeletal phenotypes in secreted frizzled-related protein 4 gene knockout mice mimic skeletal architectural abnormalities in subjects with Pyle’s disease from SFRP4 mutations

A novel variant in GNPNAT1 gene causing a spondylo‐epi‐metaphyseal dysplasia resembling PGM3—Desbuquois like dysplasia

Gene Therapy in Orthopaedics: Progress and Challenges in Pre-Clinical Development and Translation

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