BMP4 loss-of-function mutations in developmental eye disorders including SHORT syndrome

Reis, Linda M.; Tyler, Rebecca C.; Schilter, Kala F.; Abdul‐Rahman, Omar; Innis, Jeffrey W.; Kozel, Beth A.; Schneider, Adele; Bardakjian, Tanya; Lose, Edward J.; Martin, Donna M.; Broeckel, Ulrich; Semina, Elena V.

doi:10.1007/s00439-011-0968-y

Cited by 95 publications

(115 citation statements)

References 34 publications

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“…Prior screening by Sanger sequencing excluded mutations in PITX2 , FOXC1 , BMP4 , CYP1B1 , FOXE3 , and NDP (Reis et al. 2011, 2012, and unpublished data).…”

Section: Resultsmentioning

confidence: 68%

Identification of an Alu‐repeat‐mediated deletion of OPTN upstream region in a patient with a complex ocular phenotype

Schilter

Reis

Сорокина

et al. 2015

Molec Gen & Gen Med

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Genetic causes of ocular conditions remain largely unknown. To reveal the molecular basis for a congenital ocular phenotype associated with glaucoma we performed whole‐exome sequencing (WES) and whole‐genome copy number analyses of patient DNA. WES did not identify a causative variant. Copy number variation analysis identified a deletion of 10p13 in the patient and his unaffected father; the deletion breakpoint contained a single 37‐bp sequence that is normally present in two distinct Alu repeats separated by ~181 kb. The deletion removed part of the upstream region of optineurin (OPTN) as well as the upstream sequence and two coding exons of coiled‐coil domain containing 3 (CCDC3); analysis of the patient's second allele showed normal OPTN and CCDC3 sequences. Studies of zebrafish orthologs identified expression in the developing eye for both genes. OPTN is a known factor in dominant adult‐onset glaucoma and Amyotrophic Lateral Sclerosis (ALS). The deletion eliminates 98 kb of the OPTN upstream sequence leaving only ~1 kb of the proximal promoter region. Comparison of transcriptional activation capability of the 3 kb normal and the rearranged del(10)(p13) OPTN promoter sequences demonstrated a statistically significant decrease for the deleted allele; sequence analysis of the entire deleted region identified multiple conserved elements with possible cis‐regulatory activity. Additional screening of CCDC3 indicated that heterozygous loss‐of‐function alleles are unlikely to cause congenital ocular disease. In summary, we report the first regulatory region deletion involving OPTN, caused by Alu‐mediated nonallelic homologous recombination and possibly contributing to the patient's ocular phenotype. In addition, our data indicate that Alu‐mediated rearrangements of the OPTN upstream region may represent a new source of affected alleles in human conditions. Evaluation of the upstream OPTN sequences in additional ocular and ALS patients may help to determine the role of this region, if any, in human disease.

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“…Prior screening by Sanger sequencing excluded mutations in PITX2 , FOXC1 , BMP4 , CYP1B1 , FOXE3 , and NDP (Reis et al. 2011, 2012, and unpublished data).…”

Section: Resultsmentioning

confidence: 68%

Identification of an Alu‐repeat‐mediated deletion of OPTN upstream region in a patient with a complex ocular phenotype

Schilter

Reis

Сорокина

et al. 2015

Molec Gen & Gen Med

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“…Patients were screened as previously described using TaqMan assays (Applied Biosystems/Life Technologies, Carlsbad, CA, USA) for the PITX2 and FOXC1 regions and/or Affymetrix Genome-Wide Human SNP Array 6.0 (Affymetrix, Santa Clara, CA, USA); 19,26 clinical Agilent 105K oligonucleotide array (Agilent Technologies, Santa Clara, CA, USA) and Affymetrix 6.0 array data were used for one patient each (cases 21 and 27, respectively). The following PITX2 probes were used for TaqMan assays: Hs00452261_cn (P1, located in the last exon of PITX2), Hs00958157_cn (P2, PITX2C promoter), Hs01402614_cn (P3, most 5' PITX2 exon, exon 1A), Hs06705585_cn (P3B, located at B50 kb upstream of PITX2), Hs04822300_cn (P4, located 110 366 kb 5' of PITX2), Hs04838001_cn (P5, located 284 481 kb 5' of PITX2), and Hs04811562_cn (P6, located 649 476 upstream of PITX2).…”

Section: Taqman Assays and Affymetrix Copy Number Analysesmentioning

confidence: 99%

“…Several previously reported polymorphisms were observed in both patient and control populations. Genomic analysis identified deletions involving the FOXC1-coding region in three probands with ARS (cases [25][26][27] as well as the case of De Hauwere syndrome (case 28) 22 (Table 2, Figure 3). Deletion size ranged from at least 0.98 Mb to at least 1.5 Mb, deleting between 2 and 11 genes.…”

Section: Foxc1 Mutations: Phenotypes and Genotypesmentioning

confidence: 99%

PITX2 and FOXC1 spectrum of mutations in ocular syndromes

Reis¹,

Tyler²,

et al. 2012

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Anterior segment dysgenesis (ASD) encompasses a broad spectrum of developmental conditions affecting anterior ocular structures and associated with an increased risk for glaucoma. Various systemic anomalies are often observed in ASD conditions such as Axenfeld-Rieger syndrome (ARS) and De Hauwere syndrome. We report DNA sequencing and copy number analysis of PITX2 and FOXC1 in 76 patients with syndromic or isolated ASD and related conditions. PITX2 mutations and deletions were found in 24 patients with dental and/or umbilical anomalies seen in all. Seven PITX2-mutant alleles were novel including c.708_730del, the most C-terminal mutation reported to date. A second case of deletion of the distant upstream but not coding region of PITX2 was identified, highlighting the importance of this recently discovered mechanism for ARS. FOXC1 deletions were observed in four cases, three of which demonstrated hearing and/or heart defects, including a patient with De Hauwere syndrome; no nucleotide mutations in FOXC1 were identified. Review of the literature identified several other patients with 6p25 deletions and features of De Hauwere syndrome. The 1.3-Mb deletion of 6p25 presented here defines the critical region for this phenotype and includes the FOXC1, FOXF2, and FOXQ1 genes. In summary, PITX2 or FOXC1 disruptions explained 63% of ARS and 6% of other ASD in our cohort; all affected patients demonstrated additional systemic defects with PITX2 mutations showing a strong association with dental and/or umbilical anomalies and FOXC1 with heart and hearing defects. FOXC1 deletion was also found to be associated with De Hauwere syndrome.

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“…Moreover, we found that examining RNAi phenotypes at several different developmental time points and contrasting the results of maternal and zygotic knockdown studies were crucial to understanding the roles of Delta in cricket embryogenesis. Following the progression of the Dl RNAi phenotype over time allowed us to detect tissue-specific effects on neural development, as well as generic developmental delays, which are a common feature of lossof-function mutations in Notch pathway members (Ballard et al, 2010;Julian et al, 2010;Reis et al, 2011). These observations helped us to distinguish such neural and developmental delay phenotypes from specific effects on segmentation.…”

Section: Implications For the Evolution Of Segmentationmentioning

confidence: 99%

Notch/Delta signalling is not required for segment generation in the basally branching insectGryllus bimaculatus

et al. 2011

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SUMMARYArthropods and vertebrates display a segmental body organisation along all or part of the anterior-posterior axis. Whether this reflects a shared, ancestral developmental genetic mechanism for segmentation is uncertain. In vertebrates, segments are formed sequentially by a segmentation 'clock' of oscillating gene expression involving Notch pathway components. Recent studies in spiders and basal insects have suggested that segmentation in these arthropods also involves Notch-based signalling. These observations have been interpreted as evidence for a shared, ancestral gene network for insect, arthropod and bilaterian segmentation. However, because this pathway can play multiple roles in development, elucidating the specific requirements for Notch signalling is important for understanding the ancestry of segmentation. Here we show that Delta, a ligand of the Notch pathway, is not required for segment formation in the cricket Gryllus bimaculatus, which retains ancestral characteristics of arthropod embryogenesis. Segment patterning genes are expressed before Delta in abdominal segments, and Delta expression does not oscillate in the pre-segmental region or in formed segments. Instead, Delta is required for neuroectoderm and mesectoderm formation; embryos missing these tissues are developmentally delayed and show defects in segment morphology but normal segment number. Thus, what initially appear to be 'segmentation phenotypes' can in fact be due to developmental delays and cell specification errors. Our data do not support an essential or ancestral role of Notch signalling in segment generation across the arthropods, and show that the pleiotropy of the Notch pathway can confound speculation on possible segmentation mechanisms in the last common bilaterian ancestor.

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BMP4 loss-of-function mutations in developmental eye disorders including SHORT syndrome

Cited by 95 publications

References 34 publications

Identification of an Alu‐repeat‐mediated deletion of OPTN upstream region in a patient with a complex ocular phenotype

Identification of an Alu‐repeat‐mediated deletion of OPTN upstream region in a patient with a complex ocular phenotype

PITX2 and FOXC1 spectrum of mutations in ocular syndromes

Notch/Delta signalling is not required for segment generation in the basally branching insectGryllus bimaculatus

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