Congenital Joint Dislocations Caused by Carbohydrate Sulfotransferase 3 Deficiency in Recessive Larsen Syndrome and Humero-Spinal Dysostosis

Hermanns, Pia; Unger, Sheila; Rossi, Antonio; Pérez-Aytés, Antonio; Cortina, H.; Bonafé, Luisa; Boccone, Loredana; Setzu, Valeria; Dutoit, M.; Sangiorgi, Luca; Pecora, Fabio; Reicherter, Kerstin; Nishimura, Gen; Spranger, J.; Zabel, Bernhard; Superti‐Furga, Andrea

doi:10.1016/j.ajhg.2008.06.022

Cited by 15 publications

(33 citation statements)

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“…Rare mutations in CHST3 that disrupt its enzymatic activity have been reported in patients with recessive skeletal abnormalities, including spondyloepiphyseal dysplasia Omani type, Larsen syndrome, humerospinal dysostosis, and chondrodysplasia with multiple dislocation (31)(32)(33)(34)(35)(36). Despite the different diagnostic labels, patients with CHST3 mutations have similar clinical characteristics and can be generally classified as spondyloepiphyseal dysplasia with congenital joint dislocation and vertebral changes as the principal features (OMIM 603799).…”

Section: Figurementioning

confidence: 99%

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Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant

Song¹,

Karasugi²,

Cheung³

et al. 2013

J. Clin. Invest.

116

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Lumbar disc degeneration (LDD) is associated with both genetic and environmental factors and affects many people worldwide. A hallmark of LDD is loss of proteoglycan and water content in the nucleus pulposus of intervertebral discs. While some genetic determinants have been reported, the etiology of LDD is largely unknown. Here we report the findings from linkage and association studies on a total of 32,642 subjects consisting of 4,043 LDD cases and 28,599 control subjects. We identified carbohydrate sulfotransferase 3 (CHST3), an enzyme that catalyzes proteoglycan sulfation, as a susceptibility gene for LDD. The strongest genome-wide linkage peak encompassed CHST3 from a Southern Chinese family-based data set, while a genome-wide association was observed at rs4148941 in the gene in a meta-analysis using multiethnic population cohorts. rs4148941 lies within a potential microRNA-513a-5p (miR-513a-5p) binding site. Interaction between miR-513a-5p and mRNA transcribed from the susceptibility allele (A allele) of rs4148941 was enhanced in vitro compared with transcripts from other alleles. Additionally, expression of CHST3 mRNA was significantly reduced in the intervertebral disc cells of human subjects carrying the A allele of rs4148941. Together, our data provide new insights into the etiology of LDD, implicating an interplay between genetic risk factors and miRNA.

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Section: Figurementioning

confidence: 99%

“…Biochemical analysis showed the majority of these mutations result in loss-of-function or severe reduction in the enzymatic activity (31,(33)(34)(35)(36). Recessive inheritance would be consistent with most rare mutations that affect enzymes.…”

Section: Figurementioning

confidence: 99%

Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant

Song¹,

Karasugi²,

Cheung³

et al. 2013

J. Clin. Invest.

116

View full text Add to dashboard Cite

show abstract

“…22 This deficiency results in a loss of cohesion of the tissue, which has been further demonstrated by the ultrastructural study showing abnormal connective tissue. 23 In the last few years, the impairment of proteoglycan synthesis has been involved in a few human connective tissue disorders, namely, (1) SED with dislocations due to CHST3 mutations responsible for a defect in carbohydrate chondroitin 6-sulfotransferase with defective sulfation of chondroitin proteoglycan, 8,24 (2) Desbuquois dysplasia due to CANT1 mutations responsible for a defect in GAG synthesis, 9,25 (3) a chondrodysplasia with joint dislocations due to mutations in IMPAD1 (inositol monophosphatase domaincontaining protein 1) encoding the Golgi resident nucleotide phosphatase gPAPP, and responsible for a defect in sulfated substrates, 26 (4) 'a Larsen-like' phenotype with cardiac defects due to B3GAT3 (galactosyltransferase) mutations 27 and affecting, through the linker synthesis defect, dermatan heparan and chondrotin sulfate proteoglycans and (5) very recently, a spondyloepimetaphyseal dysplasia with joint laxity type 1 and a spectrum of disorders affecting a broad range of skeletal and connective tissues characterized by lax skin, muscle hypotonia, joint dislocation and spinal deformity due to B3GALT6 mutations 28 (Supplementary Table).…”

Section: Discussionmentioning

confidence: 99%

Expanding the clinical spectrum of B4GALT7 deficiency: homozygous p.R270C mutation with founder effect causes Larsen of Reunion Island syndrome

et al. 2014

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First described as a variant of Larsen syndrome in Reunion Island (LRS) in the southern Indian Ocean, 'Larsen of Reunion Island syndrome' is characterized by dwarfism, hyperlaxity, multiple dislocations and distinctive facial features. It overlaps with Desbuquois dysplasia, Larsen syndrome and spondyloepiphyseal dysplasia with dislocations ascribed to CANT1, FLNB and CHST3 mutations, respectively. We collected the samples of 22 LRS cases. After exclusion of CANT1, FLNB and CHST3 genes, an exome sequencing was performed in two affected second cousins and one unaffected sister. We identified a homozygous missense mutation in B4GALT7, NM_007255.2: c.808C4T p.(Arg270Cys) named p.R270C, in the two affected cases, not present in the unaffected sister. The same homozygous mutation was subsequently identified in the remaining 20 LRS cases. Our findings demonstrate that B4GALT7 is the causative gene for LRS. The identification of a unique homozygous mutation argues in favor of a founder effect. B4GALT7 encodes a galactosyltransferase, required for the initiation of glycoaminoglycan side chain synthesis of proteoglycans. This study expands the phenotypic spectrum of B4GALT7 mutations, initially described as responsible for the progeroid variant of Ehlers-Danlos syndrome. It further supports a common physiopathological basis involving proteoglycan synthesis in skeletal disorders with dislocations.

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“…Gen CHST3 koduje enzym zaangażowany w reakcję sulfatacji chondroityny, która jest ważnym składnikiem tkanki chrzęstnej. U ludzi opisano mutacje CHST3 wywołujące wrodzone zaburzenia rozwoju układu szkieletowego (12). Gen RAB7A koduje białko będą-ce członkiem rodziny białek pełniących różnorodne funkcje w organizmach żywych, w tym również zaangażowanych w procesy związane z aktywnością komórek kościogubnych (osteoklasty).…”

Section: Markery Genetyczne Chd Owczarków Niemieckichunclassified

Genetic markers of canine hip dysplasia

Krzemińska¹,

Gogulski²,

Aleksiewicz³

et al. 2018

Medycyna Weterynaryjna

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Postęp genomiki zwierząt domowych, możliwość prowadzenia szerokich porównawczych analiz genomowych oraz powszechna dostępność nowoczesnych narzędzi i technik molekularnych (np. mikromacierze SNP, sekwencjonowanie DNA nowej generacji) zaowocowały identyfikacją wielu mutacji odpowiedzialnych za monogenowe choroby psów (24). Z kolei wiedza o podłożu molekularnym często występujących u psów chorób lub wad o złożonym uwarunkowaniu (np. otyłość, cukrzyca typu 2, dysplazja stawu biodrowego lub łokciowego, wnętrostwo), czyli takich, które zależą od wielu genów oraz czynników środo-wiskowych, a także interakcji między nimi, nie jest tak zaawansowana. Wiedza o markerach genetycznych związanych z predyspozycją do rozwoju takich chorób lub wad jest zatem aktualnym wyzwaniem, ważnym dla wczesnej diagnostyki ryzyka ich powstania, nawet przed pojawieniem się pierwszych objawów.Dysplazja stawu biodrowego (CHD, canine hip dysplasia) to wada rozwojowa układu szkieletowego, która zalicza się do najczęściej występującego zaburzenia u psów. Na rozwój tej wady wpływają zarówno czynniki środowiskowe, jak i geny. Do głównych czynników pozagenetycznych sprzyjających rozwojowi CHD zalicza się m.in.: wysoką masę urodzeniową, nadmierne karmienie prowadzące do szybkiego wzrostu masy ciała, nadmierną suplementację wapniem czy wczesną sterylizację, a także zbyt intensywne obciąże-nie ruchowe psa w okresie wzrostu (16). Najbardziej dynamiczny rozwój tej wady ma miejsce w przedziale wiekowym od 4 do 10 miesięcy. U rosnących szczeniąt pojawiają się początkowo zaburzenia w obrębie elementów łącznotkankowych stawu biodrowego oraz mięśni pasa miednicowego. Prowadzą one do niewłaściwego rozkładu sił przenoszonych w stawie biodrowym i są przyczyną inkogruencji powierzchni stawowych. Sugeruje się również, że CHD jest procesem dynamicznym, w trakcie którego możliwe jest rozróżnienie dysplazji miednicy (dotyczącej nieprawidłowości panewek) od dysplazji kości udowej, cha- Krzemińska P., Gogulski M., Aleksiewicz R., Świtoński M. Genetic markers of canine hip dysplasiaSummary Canine hip dysplasia is a complex skeletal malformation caused by genetic and environmental factors. The prevalence of hip dysplasia in different canine breeds ranges widely, from 1% (for Whippet and Borzoi) to over 70% (for Bulldog and Pug). These differences indicate the presence of genetic variants predisposing to or preventing this disorder in gene pools of particular breeds. The importance of genetic factors is also confirmed by a high coefficient of heritability (h 2 ) of canine hip dysplasia, which for most breeds oscillates around 0.5-0.6. Application of modern genomic methods, that is, mainly genome scanning (based previously on microsatellite markers and currently on SNP microarrays) has led in recent years to the identification of potential genetic markers associated with this disorder. Such studies were carried out mostly in two breeds: Labrador retriever and German shepherd. Some of the markers were found in the vicinity of genes involved in skeletal development. Followin...

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Congenital Joint Dislocations Caused by Carbohydrate Sulfotransferase 3 Deficiency in Recessive Larsen Syndrome and Humero-Spinal Dysostosis

Abstract: Table 1 contains an error in the ''patient 5'' row and the ''maternal CHST3 allele'' column. The mutation should be described as c.617-618 TC/GA, F206X (not c.617-618 TC/CA, F206X).

Cited by 15 publications

References 0 publications

Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant

Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant

Expanding the clinical spectrum of B4GALT7 deficiency: homozygous p.R270C mutation with founder effect causes Larsen of Reunion Island syndrome

Genetic markers of canine hip dysplasia

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