De novo mutations in sporadic deletional Duchenne muscular dystrophy (DMD) cases

Mukherjee, Moumita; Chaturvedi, Lakshmi S.; Srivastava, Smriti; Mittal, Radhey Shyam; Mittal, Balraj

doi:10.1038/emm.2003.16

Cited by 21 publications

(10 citation statements)

References 11 publications

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“…The carrier rate of deletion mutations was 60%, while that of the other classes of mutations ranged from 75 to 86% (Table 1 ). Our data was also consistent with Haldane’s theoretical model of de novo mutations in X-linked diseases, as well as research in this field [ 26 , 27 ], even though several smaller number studies showed that the carrier rate is much lower than the expected theoretical value [ 28 – 30 ].…”

Section: Discussionsupporting

confidence: 91%

Comprehensive genetic characteristics of dystrophinopathies in China

Zhang

et al. 2018

Orphanet J Rare Dis

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BackgroundDystrophinopathies are a set of severe and incurable X-linked neuromuscular disorders caused by mutations in the dystrophin gene (DMD). These mutations form a complex spectrum. A national registration network is essential not only to provide more information about the prevalence and natural history of the disease, but also to collect genetic data for analyzing the mutational spectrum. This information is extremely beneficial for basic scientific research, genetic diagnosis, trial planning, clinical care, and gene therapy.MethodsWe collected data from 1400 patients (1042 patients with confirmed unrelated Duchenne muscular dystrophy [DMD] or Becker muscular dystrophy [BMD]) registered in the Chinese Genetic Disease Registry from March 2012 to August 2017 and analyzed the genetic mutational characteristics of these patients.ResultsLarge deletions were the most frequent type of mutation (72.2%), followed by nonsense mutations (11.9%), exon duplications (8.8%), small deletions (3.0%), splice-site mutations (2.1%), small insertions (1.3%), missense mutations (0.6%), and a combination mutation of a deletion and a duplication (0.1%). Exon 45–50 deletion was the most frequent deletion type, while exon 2 duplication was the most common duplication type. Two deletion hotspots were calculated—one located toward the central part (exon 45–52) of the gene and the other toward the 5’end (exon 8–26). We found no significant difference between hereditary and de novo mutations on deletion hotspots. Nonsense mutations accounted for 62.9% of all small mutations (197 patients).ConclusionWe built a comprehensive national dystrophinopathy mutation database in China, which is essential for basic and clinical research in this field. The mutational spectrum and characteristics of this DMD/BMD group were largely consistent with those in previous international DMD/BMD studies, with some differences. Based on our results, about 12% of DMD/BMD patients with nonsense mutations may benefit from stop codon read-through therapy. Additionally, the top three targets for exon-skipping therapy are exon 51 (141, 13.5%), exon 53 (115, 11.0%), and exon 45 (84, 8.0%).Electronic supplementary materialThe online version of this article (10.1186/s13023-018-0853-z) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 91%

Comprehensive genetic characteristics of dystrophinopathies in China

Zhang

et al. 2018

Orphanet J Rare Dis

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“…Families with DMD history showed anxiety and depression and strongly requested prenatal diagnosis. It has been known that 1/3 sporadic mutations of DMD gene occurs in male patients . Germinal mosaicism cases were detected in some DMD families .…”

Section: Discussionmentioning

confidence: 99%

A retrospective analysis of 237 Chinese families with Duchenne muscular dystrophy history and strategies of prenatal diagnosis

Xü

Liu

Song

et al. 2018

Clinical Laboratory Analysis

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“…We did not find a single TCF8 mutation shared by multiple families that might indicate a hotspot for mutation, and amplification of a simple-sequence repeat is not involved. One alternative basis for a high de novo mutation frequency would be reduced reproductive fitness of the mutant allele(s), but PPCD does not cause the kind of death or disability before reproductive age that is seen in some other disorders with many reports of germline mosaicism and de novo mutation such as DMD (Bullock et al 1996;Mukherjee et al 2003;Ferreiro et al 2004). It is interesting to note that, in the one family in which the mutation has been transmitted to progeny across four generations, the deletion is the most C-terminal of the mutations, which would leave most of the functional domains intact if the gene product is, indeed, produced ( fig.…”

Section: De Novo Mutationsmentioning

confidence: 99%

Mutations in TCF8 Cause Posterior Polymorphous Corneal Dystrophy and Ectopic Expression of COL4A3 by Corneal Endothelial Cells

Krafchak

Pawar

Moroi

et al. 2005

The American Journal of Human Genetics

160

208

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Posterior polymorphous corneal dystrophy (PPCD, also known as PPMD) is a rare disease involving metaplasia and overgrowth of corneal endothelial cells. In patients with PPCD, these cells manifest in an epithelial morphology and gene expression pattern, produce an aberrant basement membrane, and, sometimes, spread over the iris and nearby structures in a way that increases the risk for glaucoma. We previously mapped PPCD to a region (PPCD3) on chromosome 10 containing the gene that encodes the two-handed zinc-finger homeodomain transcription factor TCF8. Here, we report a heterozygous frameshift mutation in TCF8 that segregates with PPCD in the family used to map PPCD3 and four different heterozygous nonsense and frameshift mutations in TCF8 in four other PPCD probands. Family reports of inguinal hernia, hydrocele, and possible bone anomalies in affected individuals suggest that individuals with TCF8 mutations should be examined for nonocular anomalies. We detect transcripts of all three identified PPCD genes (VSX1, COL8A2, and TCF8) in the cornea. We show presence of a complex (core plus secondary) binding site for TCF8 in the promoter of Alport syndrome gene COL4A3, which encodes collagen type IV alpha 3, and we present immunohistochemical evidence of ectopic expression of COL4A3 in corneal endothelium of the proband of the original PPCD3 family. Identification of TCF8 as the PPCD3 gene provides a valuable tool for the study of critical gene regulation events in PPCD pathology and suggests a possible role for TCF8 mutations in altered structure and function of cells lining body cavities other than the anterior chamber of the eye. Thus, this study has identified TCF8 as the gene responsible for approximately half of the cases of PPCD, has implicated TCF8 mutations in developmental abnormalities outside the eye, and has presented the TCF8 regulatory target, COL4A3, as a key, shared molecular component of two different diseases, PPCD and Alport syndrome.

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De novo mutations in sporadic deletional Duchenne muscular dystrophy (DMD) cases

Cited by 21 publications

References 11 publications

Comprehensive genetic characteristics of dystrophinopathies in China

Comprehensive genetic characteristics of dystrophinopathies in China

A retrospective analysis of 237 Chinese families with Duchenne muscular dystrophy history and strategies of prenatal diagnosis

Mutations in TCF8 Cause Posterior Polymorphous Corneal Dystrophy and Ectopic Expression of COL4A3 by Corneal Endothelial Cells

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