Improvement of the skeletal phenotype in a mouse model of diastrophic dysplasia after postnatal treatment with N-acetylcysteine

Paganini, Chiara; Tota, Chiara Gramegna; Monti, Luca; Monti, Ilaria; Maurizi, Antonio; Capulli, Mattia; Bourmaud, Morgane; Teti, Anna; Cohen‐Solal, Martine; Villani, Simona; Forlino, Antonella; Superti‐Furga, Andrea; Rossi, Antonio

doi:10.1016/j.bcp.2021.114452

Cited by 11 publications

(11 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Early administration of NAC is known to be very effective in preventing liver injury in acetaminophen overdose, 36 and due to its role as an alternative sulfation source in cartilage, 7,37 NAC is also seen as a possible treatment for SLC26A2 ‐related skeletal dysplasia 9,38 . Intravenous NAC administration in our patient restored plasma sulfate levels, demonstrating that NAC is indeed a source of free sulfate, including extracellular sulfate, and perhaps explaining its efficacy in preventing acetaminophen hepatotoxicity, an action currently attributed solely to the replenishment of anti‐oxidant glutathione 36 .…”

Section: Discussionmentioning

confidence: 71%

See 1 more Smart Citation

Biallelic variants in the SLC13A1 sulfate transporter gene cause hyposulfatemia with a mild spondylo‐epi‐metaphyseal dysplasia

et al. 2022

Self Cite

View full text Add to dashboard Cite

Sulfate is the fourth most abundant anion in human plasma but is not measured in clinical practice and little is known about the consequences of sulfate deficiency.Nevertheless, sulfation plays an essential role in the modulation of numerous compounds, including proteoglycans and steroids. We report the first patient with a homozygous loss-of-function variant in the SLC13A1 gene, encoding a renal and intestinal sulfate transporter, which is essential for maintaining plasma sulfate levels.The homozygous (Arg12Ter) variant in SLC13A1 was found by exome sequencing performed in a patient with unexplained skeletal dysplasia. The main clinical features were enlargement of joints and spondylo-epi-metaphyseal radiological abnormalities in early childhood, which improved with age. In addition, autistic features were noted. We found profound hyposulfatemia due to complete loss of renal sulfate reabsorption. Cholesterol sulfate was reduced. Intravenous N-acetylcysteine administration temporarily restored plasma sulfate levels. We conclude that loss of the SLC13A1 gene leads to profound hypersulfaturia and hyposulfatemia, which is mainly associated with abnormal skeletal development, possibly predisposing to degenerative bone and joint disease. The diagnosis might be easily missed and more frequent.

show abstract

Section: Discussionmentioning

confidence: 71%

“…Then samples were incubated overnight at 37°C in the dark and stored at −20°C until analysis. Disaccharides analysis was carried out by HPLC using a LiChroCART 250–4 Superspher 100 RP‐18 endcapped column (Merck) as previously reported 9 …”

Section: Methodsmentioning

confidence: 99%

Biallelic variants in the SLC13A1 sulfate transporter gene cause hyposulfatemia with a mild spondylo‐epi‐metaphyseal dysplasia

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…Then papain was inactivated at 100 • C for 10 min and released GAGs were recovered by cetylpyridinium chloride precipitation as previously described [33]. Recovered GAGs were digested with 20 mU of chondroitinase ABC (AMSBIO, Abingdon, UK) and 20 mU of chondroitinase ACII (Sigma-Aldrich, Milan, Italy) in 0.1 M of ammonium acetate buffer, pH 7.35, and released chondroitin sulfate disaccharides analyzed by HPLC after 2-aminoacridone (Invitrogen, Thermo Fisher, Waltham, MA, USA) derivatization as previously described [44,45].…”

Section: Proteoglycan Sulfation Analysismentioning

confidence: 99%

Phenotypic Characterization of Immortalized Chondrocytes from a Desbuquois Dysplasia Type 1 Mouse Model: A Tool for Studying Defects in Glycosaminoglycan Biosynthesis

Tota

Valenti

Forlino

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

The complexity of skeletal pathologies makes use of in vivo models essential to elucidate the pathogenesis of the diseases; nevertheless, chondrocyte and osteoblast cell lines provide relevant information on the underlying disease mechanisms. Due to the limitations of primary chondrocytes, immortalized cells represent a unique tool to overcome this problem since they grow very easily for several passages. However, in the immortalization procedure the cells might lose the original phenotype; thus, these cell lines should be deeply characterized before their use. We immortalized primary chondrocytes from a Cant1 knock-out mouse, an animal model of Desbuquois dysplasia type 1, with a plasmid expressing the SV40 large and small T antigen. This cell line, based on morphological and biochemical parameters, showed preservation of the chondrocyte phenotype. In addition reduced proteoglycan synthesis and oversulfation of glycosaminoglycan chains were demonstrated, as already observed in primary chondrocytes from the Cant1 knock-out mouse. In conclusion, immortalized Cant1 knock-out chondrocytes maintained the disease phenotype observed in primary cells validating the in vitro model and providing an additional tool to further study the proteoglycan biosynthesis defect. The same approach might be extended to other cartilage disorders.

show abstract

“…This facilitated the development of disease-specific treatments for some of the skeletal dysplasias in this new era of precision medicine. Today we continue to benefit from Dr. McKusick's careful attention to describe the natural history of the conditions he studied, particularly achondroplasia (Murdoch et al, 1970), the lysosomal storage diseases (McKusick, 1965(McKusick, , 1969Melhern et al, 1973) and other short stature dysplasias (Kopits et al, 1974;McKusick et al, 1964McKusick et al, , 1965Walker et al, 1972) highlighted in this manuscript.…”

Section: Introductionmentioning

confidence: 98%

Current state of the art in treatment of Mendelian disease: Skeletal dysplasias

Hoover‐Fong

2021

American J of Med Genetics Pt A

View full text Add to dashboard Cite

The current state of the art in treatment of Mendelian disease, specifically skeletal dysplasias, benefits tremendously from Dr. Victor McKusick's early delineation and standardization of the nomenclature surrounding these conditions. Through close observation and careful description of each dysplasia to flesh out the nosologic backbone of the genetic skeletal disorders, individuals with the same diagnosis were identified and grouped together for genetic interrogation. These efforts have resulted in the identification of the genetic etiology of nearly all recognized skeletal disorders. This, in turn, is leading to disease‐specific treatment for many of the skeletal dysplasias in this new era of precision medicine. Furthermore, Dr. McKusick's natural history descriptions of many genetic skeletal disorders helped to establish the baseline disease state against which the effect of new treatment is compared.

show abstract

Improvement of the skeletal phenotype in a mouse model of diastrophic dysplasia after postnatal treatment with N-acetylcysteine

Cited by 11 publications

References 33 publications

Biallelic variants in the SLC13A1 sulfate transporter gene cause hyposulfatemia with a mild spondylo‐epi‐metaphyseal dysplasia

Biallelic variants in the SLC13A1 sulfate transporter gene cause hyposulfatemia with a mild spondylo‐epi‐metaphyseal dysplasia

Phenotypic Characterization of Immortalized Chondrocytes from a Desbuquois Dysplasia Type 1 Mouse Model: A Tool for Studying Defects in Glycosaminoglycan Biosynthesis

Current state of the art in treatment of Mendelian disease: Skeletal dysplasias

Contact Info

Product

Resources

About