Heterozygous aggrecan variants are associated with short stature and brachydactyly: Description of 16 probands and a review of the literature

Sentchordi-Montané, Lucía; Aza‐Carmona, Miriam; Benito‐Sanz, Sara; Ac, Barreda-Bonis; Sánchez-Garre, C.; Prieto-Matos, Pablo; Ruiz-Ocaña, Pablo; Lechuga-Sancho, Alfonso M.; Carcavilla-Urquí, A; Mulero-Collantes, Inés; Martos‐Moreno, Gabriel Ángel; A, Del Pozo; Vallespín, Elena; Offiah, A.C.; Parrón‐Pajares, Manuel; Dinis, Isabel; Sb, Sousa; Ros-Pérez, Purificación; González‐Casado, Isabel; Heath, Karen E.

doi:10.1111/cen.13581

Cited by 39 publications

(49 citation statements)

References 16 publications

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“…Polymorphisms in CTBP2 and DPP4 were discovered in GWAS for CHD and these genes were expressed in the hip tissues (although not differentially), but candidate gene TRIM expression was not detected. Of the genes associated with DDHH, CX3CR1 , RAB7A , CHSY1 , ADAMS17 , DKK1 , HOXB9 , and LMNB1 were expressed, but not differentially.…”

Section: Resultsmentioning

confidence: 99%

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Gene expression in hip soft tissues in incipient canine hip dysplasia and osteoarthritis

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Garrison

Jordan

et al. 2018

Journal Orthopaedic Research

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Canine hip dysplasia and developmental dysplasia of the human hip share demographic, phenotypic, and clinical features including the predisposition to develop osteoarthritis in affected joints. To support the results of genetic mapping studies for CHD and its concomitant osteoarthritis with functional information, we performed RNA-seq on hip capsule and teres ligament of affected and unaffected dogs. RNA seq showed that expressed genes segregated according age, capsule or ligament, and hip phenotype. Expression of HHIP, DACT2, and WIF1 was significantly higher in capsule from control hips than dysplastic hips indicating a disruption of the hedgehog signaling pathway. Expression of SPON 1, a key component of the WNT pathway, was increased significantly in both dysplastic capsule and ligament while FBN2 and EMILIN3 were significantly increased in dysplastic capsule. Of genes associated with human hip osteoarthritis, expression of ACAN, IGF1, CILP2, COL11A1, COL8A1, and HAPLN was increased significantly in dysplastic capsule. The significant increase in expression of PLA2F, TNFRSF, TMEM, and IGFBP in dysplastic capsule indicated an injury response. Gene set enrichment analysis revealed that genes involved in extracellular matrix structure, epithelial to mesenchymal transition, myogenesis, growth factor signaling, cancer and immune pathways were enriched in dysplastic capsule. For teres ligament from dysplastic joints, genes in retinoic signaling pathways and those encoding extracellular matrix molecules, but not proteoglycans, were enriched. Hip tissues respond to abnormal mechanics early in dysplastic hip development and these pathways present targets for intervention in the early synovitis and capsulitis secondary to canine and human hip dysplasia. ß

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Section: Resultsmentioning

confidence: 99%

“…The expression of ACAN , which encodes the core protein of aggrecan, was twofold elevated in dysplastic capsule compared to control capsule, and indicates a metaplastic response of the capsular fibroblast. ACAN variants have been associated with body height and growth in several species, including human …”

Section: Discussionmentioning

confidence: 99%

Gene expression in hip soft tissues in incipient canine hip dysplasia and osteoarthritis

Todhunter

Garrison

Jordan

et al. 2018

Journal Orthopaedic Research

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“…Thus, normal hand length is an important clinical sign to help in the differentiation of SHOX deficiency disorders from other mild skeletal dysplasias due to mutations in NPR2, ACAN, NPPC, or IHH. [29][30][31][32][33] We also examined the X-rays of the children to assess the presence of Madelung deformity and other suggestive signs of SHOX haploinsufficiency.…”

Section: Discussionmentioning

confidence: 99%

SHOX Deficiency in Argentinean Cohort: Long-Term Auxological Follow-Up and a Family's New Mutation

et al. 2019

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A cohort study on the growth of 19 Argentinean children, aged 0 to 18 years, and 11 of their first-degree relatives with alterations in the SHOX gene or its regulatory regions is reported. Children are born shorter and experience a growth delay during childhood with a stunted pubertal growth spurt. Body disproportion, with a sitting height/height ratio above +2 standard deviation score (SDS), was already present as early as 2 years old. Hand length was normal. Shortening of the radius, with a length below –1.9 SDS, was the earliest and most frequent radiological sign detected as early as 45 days old. We found a previously unreported mutation in a family with a highly variable phenotype, the boy had a severe phenotype with a milder presentation in other affected members of the family. We conclude that body disproportion and a shorter radius length on X-ray are useful tools for selecting children to undergo SHOX molecular studies.

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“…We identified a novel heterozygous variant (c.910G>A; A B p.Asp304Asn) in Korean family with short stature and mild delayed bone age. To date, there have been 55 families with 54 ACAN heterozygous variants in the literature and in this study [2,5,[7][8][9][10][11][12][13][14]. The previous ACAN mutations were distributed across intron 1 to exon 17, and almost all variants were located in globular domains G1 to G3.…”

Section: Discussionmentioning

confidence: 91%

Identification of a novel heterozygous mutation of ACAN in a Korean family with proportionate short stature

et al. 2018

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Aggrecan is a proteoglycan in the extracellular matrix of growth plate and cartilaginous tissues. Aggrecanopathy has been reported as a genetic cause not only for severe skeletal dysplasia but also for autosomal dominant short stature with normal to advanced bone age. We report a novel heterozygous mutation of ACAN in a Korean family with proportionate short stature identified through targeted exome sequencing. We present a girl of 4 years and 9 months with a family history of short stature over three generations. The paternal grandmother is 143 cm tall (-3.8 as a Korean standard deviation score [SDS]), the father 155 cm (-3.4 SDS), and the index case 96.2 cm (-2.9 SDS). Evaluation for short stature showed normal growth hormone (GH) peaks in the GH provocation test and a mild delayed bone age for chronological age. This subject had clinical characteristics including a triangular face, flat nasal bridge, prognathia, blue sclerae, and brittle teeth. The targeted exome sequencing was applied to detect autosomal dominant growth palate disorder. The novel variant c.910G>A (p.Asp304Asn) in ACAN was identified and this variant was found in the subject's father using Sanger sequencing. This is the first case of Korean familial short stature due to ACAN mutation. ACAN should be considered for proportionate idiopathic short stature, especially in cases of familial short stature.

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Heterozygous aggrecan variants are associated with short stature and brachydactyly: Description of 16 probands and a review of the literature

Cited by 39 publications

References 16 publications

Gene expression in hip soft tissues in incipient canine hip dysplasia and osteoarthritis

Gene expression in hip soft tissues in incipient canine hip dysplasia and osteoarthritis

SHOX Deficiency in Argentinean Cohort: Long-Term Auxological Follow-Up and a Family's New Mutation

Identification of a novel heterozygous mutation of ACAN in a Korean family with proportionate short stature

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