Deletion of Exon 1 in AMER1 in Osteopathia Striata with Cranial Sclerosis

Osteopathia striata with cranial sclerosis (OSCS) is an X-linked dominant condition characterised by metaphyseal striations, macrocephaly, cleft palate, and developmental delay in affected females. Males have a more severe phenotype with multi-organ malformations, and rarely survive. To date, only frameshift and nonsense variants in exon 2, the single coding exon of AMER1, or whole gene deletions have been reported to cause OSCS. In this study, we describe two families with phenotypic features typical of OSCS. Exome sequencing and multiplex ligation-dependent probe amplification (MLPA) did not identify pathogenic variants in AMER1. Therefore, genome sequencing was employed which identified two deletions containing the non-coding exon 1 of AMER1 in the families. These families highlight the importance of considering variants or deletions of upstream non-coding exons in conditions such as OSCS, noting that often such exons are not captured on probe or enrichment-based platforms because of their high G/C content.

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Molecular characterization of novel germline deletions affecting SDHD and SDHC in pheochromocytoma and paraganglioma patients

Endocrine Related Cancer ◽

10.1677/erc-09-0084 ◽

2009 ◽

Vol 16 (3) ◽

pp. 929-937 ◽

Cited By ~ 13

Author(s):

Jean-Pierre Bayley ◽

Marjan M Weiss ◽

Anneliese Grimbergen ◽

Bernadette T J van Brussel ◽

Frederik J Hes ◽

...

Keyword(s):

Nonsense Mutations ◽

Gene Deletions ◽

Exon 2 ◽

Gene Insertion ◽

Large Deletions ◽

Exon 1 ◽

Long Range Pcr ◽

Intron 2 ◽

Dependent Probe

A major cause of paraganglioma and pheochromocytoma is germline mutation of the tumor suppressor genes SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH). While many SDH missense/nonsense mutations have been identified, few large deletions have been described. We performed multiplex ligation-dependent probe amplification deletion analysis in 126 point mutation-negative patients, and here we describe four novel deletions of SDHD and SDHC. Long-range PCR was used for the fine mapping of deletions. One patient had a 10 kb AluSg–AluSx-mediated deletion including SDHD exons 1 and 2, the entire TIMM8B gene, and deletion of exons of C11orf57. A second patient had a deletion of SDHD exons 1 and 2 and exon 1 of the TIMM8B gene. A third patient showed a deletion of exon 2 of SDHD, together with a 235 bp MIRb–Tensin gene insertion. In a fourth patient, a deletion of exons 5 and 6 of the SDHC gene was found, only the second SDHC deletion currently known. The deletions of the TIMM8B and C11orf57 genes are the first to be described, but do not appear to result in an additional phenotype in these patients. Four of the eight breakpoints occurred in Alu sequences and all three SDHD deletions showed an intron 2 breakpoint. This study underlines the fact that clinically relevant deletions may encompass neighboring genes, with the potential to modify phenotype. Gene deletions of SDHD and SDHC represent a substantial proportion of all mutations, and must be considered in paraganglioma patients shown to be negative for mutations by sequencing.

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Whole Exome Sequencing Provides the Correct Diagnosis in a Case of Osteopathia Striata with Cranial Sclerosis: Case Report of a Novel Frameshift Mutation in AMER1

Journal of Pediatric Genetics ◽

10.1055/s-0040-1710058 ◽

2020 ◽

Author(s):

José María García-Aznar ◽

Noelia Ramírez ◽

David De Uña ◽

Elisa Santiago ◽

Lorenzo Monserrat

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Target Genes ◽

Correct Diagnosis ◽

Sotos Syndrome ◽

Pathogenic Variants ◽

Osteopathia Striata ◽

Whole Exome ◽

Cranial Sclerosis ◽

Extended Analysis

AbstractThe diagnosis of rare diseases with multisystem manifestations can constitute a difficult process that delays the determination of the underlying cause. Whole exome sequencing (WES) provides a suitable option to examine multiple target genes associated with several disorders that display common features. In this study, we report the case of a female patient suspected of having Sotos syndrome. Screening for the initially selected genes, considering Sotos syndrome and Sotos-like disorders, did not identify any pathogenic variants that could explain the phenotype. The extended analysis, which considered all genes in the exome associated with features consistent with those shown by the studied patient, revealed a novel frameshift variant in the AMER1 gene, responsible for osteopathia striata with cranial sclerosis. WES analysis and an updated revision of previously reported disease-causing mutations, proved useful to reach an accurate diagnosis and guide further examination to identify critical abnormalities.

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Osteopathia striata congenita with cranial sclerosis and intellectual disability due to contiguous gene deletions involving the WTX locus

Clinical Genetics ◽

10.1111/j.1399-0004.2012.01905.x ◽

2013 ◽

Vol 83 (3) ◽

pp. 251-256 ◽

Cited By ~ 14

Author(s):

SK Holman ◽

T Morgan ◽

G Baujat ◽

V Cormier-Daire ◽

T-J Cho ◽

...

Keyword(s):

Intellectual Disability ◽

Gene Deletions ◽

Osteopathia Striata ◽

Contiguous Gene ◽

Cranial Sclerosis

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Transcriptional Pausing and Activation at Exons-1 and -2, Respectively, Mediate the MGMT Gene Expression in Human Glioblastoma Cells

Genes ◽

10.3390/genes12060888 ◽

2021 ◽

Vol 12 (6) ◽

pp. 888

Author(s):

Mohammed A. Ibrahim Al-Obaide ◽

Kalkunte S. Srivenugopal

Keyword(s):

Dna Methyltransferase ◽

Glioblastoma Cells ◽

Rt Pcr ◽

Repair Gene ◽

Exon 2 ◽

Mgmt Gene ◽

Dna Repair Gene ◽

Exon 1 ◽

Transcriptional Pausing ◽

Transcription Assays

Background: The therapeutically important DNA repair gene O6-methylguanine DNA methyltransferase (MGMT) is silenced by promoter methylation in human brain cancers. The co-players/regulators associated with this process and the subsequent progression of MGMT gene transcription beyond the non-coding exon 1 are unknown. As a follow-up to our recent finding of a predicted second promoter mapped proximal to the exon 2 [Int. J. Mol. Sci.2021, 22(5), 2492], we addressed its significance in MGMT transcription. Methods: RT-PCR, RT q-PCR, and nuclear run-on transcription assays were performed to compare and contrast the transcription rates of exon 1 and exon 2 of the MGMT gene in glioblastoma cells. Results: Bioinformatic characterization of the predicted MGMT exon 2 promoter showed several consensus TATA box and INR motifs and the absence of CpG islands in contrast to the established TATA-less, CpG-rich, and GAF-bindable exon 1 promoter. RT-PCR showed very weak MGMT-E1 expression in MGMT-proficient SF188 and T98G GBM cells, compared to active transcription of MGMT-E2. In the MGMT-deficient SNB-19 cells, the expression of both exons remained weak. The RT q-PCR revealed that MGMT-E2 and MGMT-E5 expression was about 80- to 175-fold higher than that of E1 in SF188 and T98G cells. Nuclear run-on transcription assays using bromo-uridine immunocapture followed by RT q-PCR confirmed the exceptionally lower and higher transcription rates for MGMT-E1 and MGMT-E2, respectively. Conclusions: The results provide the first evidence for transcriptional pausing at the promoter 1- and non-coding exon 1 junction of the human MGMT gene and its activation/elongation through the protein-coding exons 2 through 5, possibly mediated by a second promoter. The findings offer novel insight into the regulation of MGMT transcription in glioma and other cancer types.

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Plasmodium vivax Cysteine-Rich Protective Antigen Polymorphism at Exon-1 Shows Recombination and Signatures of Balancing Selection

Genes ◽

10.3390/genes12010029 ◽

2020 ◽

Vol 12 (1) ◽

pp. 29

Author(s):

Lilia González-Cerón ◽

José Cebrián-Carmona ◽

Concepción M. Mesa-Valle ◽

Federico García-Maroto ◽

Frida Santillán-Valenzuela ◽

...

Keyword(s):

Amino Acid ◽

B Cell ◽

Plasmodium Vivax ◽

Nucleotide Diversity ◽

Protective Antigen ◽

Balancing Selection ◽

Southern Mexico ◽

Exon 2 ◽

Exon 1 ◽

Tajima’S D

Plasmodium vivax Cysteine-Rich Protective Antigen (CyRPA) is a merozoite protein participating in the parasite invasion of human reticulocytes. During natural P. vivax infection, antibody responses against PvCyRPA have been detected. In children, low anti-CyRPA antibody titers correlated with clinical protection, which suggests this protein as a potential vaccine candidate. This work analyzed the genetic and amino acid diversity of pvcyrpa in Mexican and global parasites. Consensus coding sequences of pvcyrpa were obtained from seven isolates. Other sequences were extracted from a repository. Maximum likelihood phylogenetic trees, genetic diversity parameters, linkage disequilibrium (LD), and neutrality tests were analyzed, and the potential amino acid polymorphism participation in B-cell epitopes was investigated. In 22 sequences from Southern Mexico, two synonymous and 21 nonsynonymous mutations defined nine private haplotypes. These parasites had the highest LD-R2 index and the lowest nucleotide diversity compared to isolates from South America or Asia. The nucleotide diversity and Tajima’s D values varied across the coding gene. The exon-1 sequence had greater diversity and Rm values than those of exon-2. Exon-1 had significant positive values for Tajima’s D, β-α values, and for the Z (HA: dN > dS) and MK tests. These patterns were similar for parasites of different origin. The polymorphic amino acid residues at PvCyRPA resembled the conformational B-cell peptides reported in PfCyRPA. Diversity at pvcyrpa exon-1 is caused by mutation and recombination. This seems to be maintained by balancing selection, likely due to selective immune pressure, all of which merit further study.

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The Identification of Mutation in BMP15 Gene Associated with Litter Size in Xinjiang Cele Black Sheep

Animals ◽

10.3390/ani11030668 ◽

2021 ◽

Vol 11 (3) ◽

pp. 668

Author(s):

Zhi-gang Niu ◽

Jin Qin ◽

Yao Jiang ◽

Xiang-Dong Ding ◽

Yu-gong Ding ◽

...

Keyword(s):

Sequence Analysis ◽

Litter Size ◽

Base Change ◽

Wild Type ◽

Wild Genotype ◽

Exon 2 ◽

Black Sheep ◽

Morphogenetic Protein ◽

Gene Sequence Analysis ◽

Exon 1

The Bone Morphogenetic Protein 15 (BMP15) gene is known to have multiple single-nucleotide polymorphism sites associated with sheep fecundity. This study used gene sequence analysis and mutation detection assays for BMP15 by using 205 blood samples of ewes with known lambing records. Sequence analysis showed that mutation B1 missed the CTT base in exon 1 at positions 28–30, leading to a leucine deletion in the BMP15 protein. Litter size of ewes differed significantly between BB and B+ genotypes of B1 (p < 0.05); however, the differences between wild genotype (++) and homozygous (BB) or wild genotype (++) and heterozygous (B+) were not significant (p > 0.05). Another mutation, T755C, is a T-to-C base change at position 755 of exon 2, resulting in leucine replacement by proline at this position of the BMP15 protein (p.L252P). Two genotypes were identified in the flock: heterozygous (E+) and wild-type genotype (++). Ewes with heterozygous (E+) p.L252P had significantly larger litter sizes than those with the wild-type genotype (p < 0.05). Comprehensive analysis suggests that p.L252P is a mutation that affects fecundity in Cele black sheep.

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Genotype-Phenotype Correlations in Neurofibromatosis Type 1: A Single-Center Cohort Study

Cancers ◽

10.3390/cancers13081879 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1879

Author(s):

Marcello Scala ◽

Irene Schiavetti ◽

Francesca Madia ◽

Cristina Chelleri ◽

Gianluca Piccolo ◽

...

Keyword(s):

Neurofibromatosis Type 1 ◽

Neurofibromatosis Type ◽

Copy Number Variations ◽

Single Nucleotide Variants ◽

Multivariate Statistical ◽

Gene Deletions ◽

Pathogenic Variants ◽

Lisch Nodules ◽

Next Generation Sequencing Ngs

Neurofibromatosis type 1 (NF1) is a proteiform genetic condition caused by pathogenic variants in NF1 and characterized by a heterogeneous phenotypic presentation. Relevant genotype–phenotype correlations have recently emerged, but only few pertinent studies are available. We retrospectively reviewed clinical, instrumental, and genetic data from a cohort of 583 individuals meeting at least 1 diagnostic National Institutes of Health (NIH) criterion for NF1. Of these, 365 subjects fulfilled ≥2 NIH criteria, including 235 pediatric patients. Genetic testing was performed through cDNA-based sequencing, Next Generation Sequencing (NGS), and Multiplex Ligation-dependent Probe Amplification (MLPA). Uni- and multivariate statistical analysis was used to investigate genotype–phenotype correlations. Among patients fulfilling ≥ 2 NIH criteria, causative single nucleotide variants (SNVs) and copy number variations (CNVs) were detected in 267/365 (73.2%) and 20/365 (5.5%) cases. Missense variants negatively correlated with neurofibromas (p = 0.005). Skeletal abnormalities were associated with whole gene deletions (p = 0.05) and frameshift variants (p = 0.006). The c.3721C>T; p.(R1241*) variant positively correlated with structural brain alterations (p = 0.031), whereas Lisch nodules (p = 0.05) and endocrinological disorders (p = 0.043) were associated with the c.6855C>A; p.(Y2285*) variant. We identified novel NF1 genotype–phenotype correlations and provided an overview of known associations, supporting their potential relevance in the implementation of patient management.

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Cranial Sclerosis with Striated Bone Disease (Osteopathia Striata)

Klinische Pädiatrie ◽

10.1055/s-2008-1033900 ◽

1986 ◽

Vol 198 (05) ◽

pp. 418-424 ◽

Cited By ~ 12

Author(s):

H. Piechowiak ◽

F. Goebel ◽

U. Hirche ◽

R. Tyrell

Keyword(s):

Bone Disease ◽

Osteopathia Striata ◽

Cranial Sclerosis

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Complete Thyroxine-Binding Globulin (TBG) Deficiency Produced by a Mutation in Acceptor Splice Site Causing Frameshift and Early Termination of Translation (TBG-Kankakee)12

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.83.10.5208 ◽

1998 ◽

Vol 83 (10) ◽

pp. 3604-3608

Author(s):

Gisah A. Carvalho ◽

Roy E. Weiss ◽

Samuel Refetoff

Keyword(s):

Splice Site ◽

Messenger Rna ◽

Restriction Site ◽

Splice Junction ◽

Early Termination ◽

Coding Region ◽

Acceptor Splice Site ◽

Exon 2 ◽

Gene Level ◽

Exon 1

Fourteen T4-binding globulin (TBG) variants have been identified at the gene level. They are all located in the coding region of the gene and 6 produce complete deficiency of TBG (TBG-CD). We now describe the first mutation in a noncoding region producing TBG-CD. The proband was treated for over 20 yr with L-T4 because of fatigue associated with a low concentration of serum total T4. Fifteen family members were studied showing low total T4 inherited as an X chromosome-linked trait, and affected males had undetectable TBG in serum. Sequencing of the entire coding region and promoter of the TBG gene revealed no abnormality. However, an A to G transition was found in the acceptor splice junction of intron II that produced a new HaeIII restriction site cosegregating with the TBG-CD phenotype. Sequencing exon 1 to exon 3 of TBG complementary DNA reverse transcribed from messenger RNA of skin fibroblasts from an affected male, confirmed a shift in the ag acceptor splice site. This results in the insertion of a G in exon 2 and causes a frameshift and a premature stop at codon 195. This early termination of translation predicts a truncated TBG lacking 201 amino acids.

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