A family with two consecutive nonsense mutations in BMPR1A causing juvenile polyposis

Howe, James R.; Chinnathambi, Sathivel; Bair, Jennifer; Pechman, Brenda; Salamon, Ágnes; Tam, Beatrix; Simon, L

doi:10.1016/j.cancergencyto.2007.11.001

Cited by 5 publications

(5 citation statements)

References 19 publications

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“…Germline mutations of BMPR1A are responsible for ∼20–60% of families with hereditary mixed polyposis syndrome (HMPS) and juvenile polyposis syndrome (JP), diseases characterized by the presence of mixed gastrointestinal polyps and an increased risk of colorectal carcinoma (Howe et al, 2004; Calva‐Cerqueira et al, 2009; Cheah et al, 2009). Interestingly, nonsense mutations in BMPR1A responsible for HMPS and JP have been documented to occur at the same residue position (Y245) as a missense mutation we identified in C078 (Howe et al, 2008; Calva‐Cerqueira et al, 2009). The Y245S mutation also lies within the ATP binding pocket of the intracellular protein kinase domain, suggesting that a disruption at this position may affect the function of BMPR1A.…”

Section: Discussionmentioning

confidence: 67%

Identification of TFG (TRK‐fused gene) as a putative metastatic melanoma tumor suppressor gene

Dutton‐Regester

Aoude

Nancarrow

et al. 2012

Genes Chromosomes & Cancer

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High density SNP arrays can be used to identify DNA copy number changes in tumors such as homozygous deletions of tumor suppressor genes and focal amplifications of oncogenes. Illumina Human CNV370 Bead chip arrays were used to assess the genome for unbalanced chromosomal events occurring in 39 cell lines derived from stage III metastatic melanomas. A number of genes previously recognized to have an important role in the development and progression of melanoma were identified including homozygous deletions of CDKN2A (13 of 39 samples), CDKN2B (10 of 39), PTEN (3 of 39), PTPRD (3 of 39), TP53 (1 of 39), and amplifications of CCND1 (2 of 39), MITF (2 of 39), MDM2 (1 of 39), and NRAS (1 of 39). In addition, a number of focal homozygous deletions potentially targeting novel melanoma tumor suppressor genes were identified. Because of their likely functional significance for melanoma progression, FAS, CH25H, BMPR1A, ACTA2, and TFG were investigated in a larger cohort of melanomas through sequencing. Nonsynonymous mutations were identified in BMPR1A (1 of 43), ACTA2 (3 of 43), and TFG (5 of 103). A number of potentially important mutation events occurred in TFG including the identification of a mini mutation "hotspot" at amino acid residue 380 (P380S and P380L) and the presence of multiple mutations in two melanomas. Mutations in TFG may have important clinical relevance for current therapeutic strategies to treat metastatic melanoma.

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Section: Discussionmentioning

confidence: 67%

Identification of TFG (TRK‐fused gene) as a putative metastatic melanoma tumor suppressor gene

Dutton‐Regester

Aoude

Nancarrow

et al. 2012

Genes Chromosomes & Cancer

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“…Eight were missense mutations, six were nonsense mutations and one was an insertion. Proband JPS88 had two consecutive substitutions in BMPR1A that resulted in two consecutive nonsense mutations, an extremely rare mutation in human disease (Table 2) (23).…”

Section: Resultsmentioning

confidence: 99%

The rate of germline mutations and large deletions of SMAD4 and BMPR1A in juvenile polyposis

et al. 2008

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Juvenile polyposis (JPS) is an autosomal dominant syndrome that predisposes individuals to develop gastrointestinal polyps and cancer. Germline point mutations in SMAD4 and BMPR1A have been identified as causing JPS in approximately 40-60% of patients, but few studies have looked at the rate of large deletions. In this study, we determined the overall prevalence of genetic changes of SMAD4 and BMPR1A by sequencing and by screening for larger deletions. DNA was extracted from 102 JPS probands, and each exon and intron-exon boundary of SMAD4 and BMPR1A were sequenced. Coding and non-coding exons of SMAD4 and BMPR1A were screened for deletions with multiplex ligation-dependent probe amplification (MLPA). By sequencing, 20 probands had point mutations of SMAD4 and 22 of BMPR1A. By MLPA, one proband had deletion of most of SMAD4, one of both BMPR1A and PTEN, one of the 5' end of BMPR1A, and another of the 5' end of SMAD4. The overall prevalence of SMAD4 and BMPR1A point mutations and deletions in JPS was 45% in the largest series of patients to date. Large deletions are less frequent in JPS patients, but represent other heritable causes of JPS, which should be screened for in pre-symptomatic genetic testing.

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“…Mutations in exon 10 are relevant in that they have been demonstrated to occur within a conserved carboxyl-terminal region of ALK-1 (the non-activating non-downregulating box (NANDOR BOX)), an alteration that may have effects on TGF-b-induced receptor signalling [54,63,66]. The finding that juvenile polyposis is associated with mutations in either SMAD4, as in the juvenile polyposishereditary telangiectasia syndrome [11], or BMPR-IA [69] further supports the importance of BMPR signalling and the potential link between HHT and PAH [69].…”

Section: Geneticsmentioning

confidence: 99%

The pulmonary vascular complications of hereditary haemorrhagic telangiectasia

Faughnan¹,

Granton²,

Young³

2009

Eur Respir J

124

116

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Hereditary haemorrhagic telangiectasia (HHT) is a rare autosomal dominant disorder, characterised by the presence of vascular malformations. The pulmonary vascular complications of HHT include pulmonary arteriovenous malformations, pulmonary hypertension associated with high-output heart failure and liver vascular malformations and, finally, pulmonary arterial hypertension secondary to HHT. In the present review, the authors describe the clinical presentation, diagnosis and management of all three pulmonary vascular presentations of HHT, as well as the underlying genetics and pathophysiology.

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A family with two consecutive nonsense mutations in BMPR1A causing juvenile polyposis

Cited by 5 publications

References 19 publications

Identification of TFG (TRK‐fused gene) as a putative metastatic melanoma tumor suppressor gene

Identification of TFG (TRK‐fused gene) as a putative metastatic melanoma tumor suppressor gene

The rate of germline mutations and large deletions of SMAD4 and BMPR1A in juvenile polyposis

The pulmonary vascular complications of hereditary haemorrhagic telangiectasia

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