A novel homozygous variant in <i>BMPR1B</i> underlies acromesomelic dysplasia Hunter–Thompson type

Ullah, Asmat; Umair, Muhammad; Muhammad, Dost; Bilal, Muhammad; Lee, Kwanghyuk; Leal, Suzanne M.; Ahmad, Farooq

doi:10.1111/ahg.12233

Cited by 14 publications

(9 citation statements)

References 20 publications

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“…Mutations in ELN cause autosomal dominant cutis laxa 40. Mutations in bone morphogenetic protein receptor type 1B (BMPR1B) underlie autosomal recessive Hunter-Thompson41 type of acromesomelic dysplasia. EGF-containing fibulin extracellular matrix protein 1 ( EFEMP1 ) has been associated with polygenic susceptibility to inguinal hernia42 and varicose veins 43 .…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms

Schafmayer¹,

Harrison²,

Buch³

et al. 2019

Gut

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ObjectiveDiverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease.DesignDiscovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry.ResultsWe discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3×10−10 and 0.002 (ORallelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33).ConclusionIn silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.

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Section: Discussionmentioning

confidence: 99%

Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms

Schafmayer¹,

Harrison²,

Buch³

et al. 2019

Gut

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“…A remarkable impact on GDF5 function can also be caused by the p. Thr444Ilefs*44 homozygous frameshift mutation that introduces a late stop codon and a potentially truncated protein with altered folding [50,56], causing Hunter-Thompson type acromesomelic chondrodysplasia [56]. Recently, a pathogenetic mutation in BMPR1B, a GDF5 receptor, has been reported as causative for the same phenotype [57].…”

Section: Discussionmentioning

confidence: 99%

“…GDF5 soluble dimers can bind to different BMPR family receptor dimers [45]. The main GDF5 receptor is BMPR1B [57]. BMP2 is another bone morphogenic protein binding and activating the BMPR1B receptor [45].…”

Section: Discussionmentioning

confidence: 99%

GDF5 mutation case report and a systematic review of molecular and clinical spectrum: Expanding current knowledge on genotype-phenotype correlations

Genovesi

Guadagnolo

Marchionni

et al. 2021

Bone

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“…It is characterised by length abnormalities in the upper limb that include short proximal and middle bones and multiple abnormalities in the carpal bones, similar presentation is seen in the lower limb, which is more severely affected and both limbs demonstrate more severe presentation distally than proximally [ 38 ]. Recent novel homozygous mutation in the BMPR1B gene has been described to cause Hunter-Thompson type, as well as those mutations originally described in GDF-5 [ 39 , 40 ].…”

Section: Introductionmentioning

confidence: 99%

“Lessons from Rare Forms of Osteoarthritis”

et al. 2021

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Osteoarthritis (OA) is one of the most prevalent conditions in the world, particularly in the developed world with a significant increase in cases and their predicted impact as we move through the twenty-first century and this will be exacerbated by the covid pandemic. The degeneration of cartilage and bone as part of this condition is becoming better understood but there are still significant challenges in painting a complete picture to recognise all aspects of the condition and what treatment(s) are most appropriate in individual causes. OA encompasses many different types and this causes some of the challenges in fully understanding the condition. There have been examples through history where much has been learnt about common disease(s) from the study of rare or extreme phenotypes, particularly where Mendelian disorders are involved. The often early onset of symptoms combined with the rapid and aggressive pathogenesis of these diseases and their predictable outcomes give an often-under-explored resource. It is these “rarer forms of disease” that William Harvey referred to that offer novel insights into more common conditions through their more extreme presentations. In the case of OA, GWAS analyses demonstrate the multiple genes that are implicated in OA in the general population. In some of these rarer forms, single defective genes are responsible. The extreme phenotypes seen in conditions such as Camptodactyly Arthropathy-Coxa Vara-pericarditis Syndrome, Chondrodysplasias and Alkaptonuria all present potential opportunities for greater understanding of disease pathogenesis, novel therapeutic interventions and diagnostic imaging. This review examines some of the rarer presenting forms of OA and linked conditions, some of the novel discoveries made whilst studying them, and findings on imaging and treatment strategies.

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A novel homozygous variant in BMPR1B underlies acromesomelic dysplasia Hunter–Thompson type

Cited by 14 publications

References 20 publications

Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms

Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms

GDF5 mutation case report and a systematic review of molecular and clinical spectrum: Expanding current knowledge on genotype-phenotype correlations

“Lessons from Rare Forms of Osteoarthritis”

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