Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces

Venselaar, Hanka; Beek, Tim A. H. te; Kuipers, Remko; Hekkelman, Maarten L.; Vriend, Gert

doi:10.1186/1471-2105-11-548

Cited by 870 publications

(711 citation statements)

References 25 publications

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“…Therefore, this change has a high potency for being pathogenic. The result of Polyphen2 and SIFT also confirms this (Kumar et al 2009;Adzhubei et al 2010;Venselaar et al 2010).…”

Section: Discussionsupporting

confidence: 74%

“…p. [(Gly18Asp)] was found to be the most common mutation which was seen in four different families. Types and frequencies of mutations are shown in Tables 3 and 4. The pathogenicity of identified mutations were checked in related websites such as Polyphen-2 (Adzhubei et al 2010), SIFT (Kumar et al 2009), and also HOPE project (Venselaar et al 2010). Results and suggested effects are shown in Table 4.…”

Section: Resultsmentioning

confidence: 99%

“…Since proline residue is smaller than leucine, this will cause a possible loss of external interactions and prevents multimeric contacts. The 225th amino acid has been shown to be 100% conserved residue (Venselaar et al 2010), and it would damage the protein if it is replaced with an arginine which is a bigger amino acid with different charge. Also, methionine in comparison with threonine at residue 237 shows differences in hydrophobicity.…”

Section: Discussionmentioning

confidence: 99%

“…This threonine residue is much conserved and also methionine is a bigger residue; therefore, it is expected that it cannot be buried in the core of the protein. In conclusion, based on the HOPE project's (Venselaar et al 2010) [(Ser163Asn)] are potentially pathogenic because they have not been reported in the single nucleotide polymorphism database (Exome Variant Server). Moreover, bioinformatics prediction by Polyphen-2 and SIFT indicated that these changes are either "probably damaging" or "damaging" with different scores (see Table 4).…”

Section: Discussionmentioning

confidence: 99%

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Molecular Characterization of QDPR Gene in Iranian Families with BH4 Deficiency: Reporting Novel and Recurrent Mutations

et al. 2015

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Newborn screening for PKU has been in practice in Iran since 2007. Some hyperphenylalaninemia cases have tetrahydrobiopterin (BH4) biosynthesis deficiency/ disorder. Several genes including QDPR (encodes DHPR enzyme, the necessary cofactor for PAH activity) have been associated with the BH4. Mutations have been previously described in the QDPR gene. The incidence of BH4 deficiency is expected to be higher in Iran due to high rate of consanguineous marriages.We identified a total of 93 BH4-deficient families. A multiplex set of STR markers linked to 4 genes responsible for the BH4 deficiency (i.e., GCH1, PCBD1, PTS, and QDPR genes) was used to quickly determine which gene may be responsible to cause the disease. Mutation analysis of QDPR gene revealed some known and novel mutations. Our findings show that no common mutation predominates, and they are scattered in the gene in our population.

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“…Therefore, this change has a high potency for being pathogenic. The result of Polyphen2 and SIFT also confirms this (Kumar et al 2009;Adzhubei et al 2010;Venselaar et al 2010).…”

Section: Discussionsupporting

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Molecular Characterization of QDPR Gene in Iranian Families with BH4 Deficiency: Reporting Novel and Recurrent Mutations

et al. 2015

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“…Four bioinformatic programs, Polyphen-2, 25 SNPs3D, 26 MutationTaster 27 and the Project HOPE web server, 28 were used to determine the predicted effect of the novel CNGA3 missense variant.…”

Section: Bioinformatic Analysismentioning

confidence: 99%

Homozygous missense variant in the human CNGA3 channel causes cone-rod dystrophy

et al. 2014

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We assessed a large consanguineous Pakistani family (PKAB157) segregating early onset low vision problems. Funduscopic and electroretinographic evaluation of affected individuals revealed juvenile cone-rod dystrophy (CRD) with maculopathy. Other clinical symptoms included loss of color discrimination, photophobia and nystagmus. Whole-exome sequencing, segregation and haplotype analyses demonstrated that a transition variant (c.955T4C; p.(Cys319Arg)) in CNGA3 co-segregated with the CRD phenotype in family PKAB157. The ability of CNGA3 channel to influx calcium in response to agonist, when expressed either alone or together with the wild-type CNGB3 subunit in HEK293 cells, was completely abolished due to p.Cys319Arg variant. Western blotting and immunolocalization studies suggest that a decreased channel density in the HEK293 cell membrane due to impaired folding and/or trafficking of the CNGA3 protein is the main pathogenic effect of the p.Cys319Arg variant. Mutant alleles of the human cone photoreceptor cyclic nucleotide-gated channel (CNGA3) are frequently associated with achromatopsia. In rare cases, variants in CNGA3 are also associated with cone dystrophy, Leber's congenital amaurosis and oligo cone trichromacy. The identification of predicted p.(Cys319Arg) missense variant in CNGA3 expands the repertoire of the known genetic causes of CRD and phenotypic spectrum of CNGA3 alleles.

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RYR1Mutations as a Cause of Ophthalmoplegia, Facial Weakness, and Malignant Hyperthermia

Shaaban¹,

Ramos‐Platt²,

Gilles³

et al. 2013

JAMA Ophthalmol

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IMPORTANCE Total ophthalmoplegia can result from ryanodine receptor 1 (RYR1) mutations without overt associated skeletal myopathy. Patients carrying RYR1 mutations are at high risk of developing malignant hyperthermia. Ophthalmologists should be familiar with these important clinical associations.OBJECTIVE To determine the genetic cause of congenital ptosis, ophthalmoplegia, facial paralysis, and mild hypotonia segregating in 2 pedigrees diagnosed with atypical Moebius syndrome or congenital fibrosis of the extraocular muscles. DESIGN, SETTING, AND PARTICIPANTS Clinical data including medical and family histories were collected at research laboratories at Boston Children's Hospital and Jules Stein Eye Institute (Engle and Demer labs) for affected and unaffected family members from 2 pedigrees in which patients presented with total ophthalmoplegia, facial weakness, and myopathy.INTERVENTION Homozygosity mapping and whole-exome sequencing were conducted to identify causative mutations in affected family members. Histories, physical examinations, and clinical data were reviewed. MAIN OUTCOME AND MEASURE Mutations in RYR1.RESULTS Missense mutations resulting in 2 homozygous RYR1 amino acid substitutions (E989G and R3772W) and 2 compound heterozygous RYR1 substitutions (H283R and R3772W) were identified in a consanguineous and a nonconsanguineous pedigree, respectively. Orbital magnetic resonance imaging revealed marked hypoplasia of extraocular muscles and intraorbital cranial nerves. Skeletal muscle biopsy specimens revealed nonspecific myopathic changes. Clinically, the patients' ophthalmoplegia and facial weakness were far more significant than their hypotonia and limb weakness and were accompanied by an unrecognized susceptibility to malignant hyperthermia.CONCLUSIONS AND RELEVANCE Affected children presenting with severe congenital ophthalmoplegia and facial weakness in the setting of only mild skeletal myopathy harbored recessive mutations in RYR1, encoding the ryanodine receptor 1, and were susceptible to malignant hyperthermia. While ophthalmoplegia occurs rarely in RYR1-related myopathies, these children were atypical because they lacked significant weakness, respiratory insufficiency, or scoliosis. RYR1-associated myopathies should be included in the differential diagnosis of congenital ophthalmoplegia and facial weakness, even without clinical skeletal myopathy. These patients should also be considered susceptible to malignant hyperthermia, a life-threatening anesthetic complication avoidable if anticipated presurgically.

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Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces

Cited by 870 publications

References 25 publications

Molecular Characterization of QDPR Gene in Iranian Families with BH4 Deficiency: Reporting Novel and Recurrent Mutations

Molecular Characterization of QDPR Gene in Iranian Families with BH4 Deficiency: Reporting Novel and Recurrent Mutations

Homozygous missense variant in the human CNGA3 channel causes cone-rod dystrophy

RYR1Mutations as a Cause of Ophthalmoplegia, Facial Weakness, and Malignant Hyperthermia

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