scholarly journals Mutational spectrum of SMPD1 gene in Pakistani Niemann-Pick disease patients

2020 ◽  
Vol 36 (3) ◽  
Author(s):  
Huma Arshad Cheema ◽  
Iqra Ghulam Rasool ◽  
Muhammad Nadeem Anjum ◽  
Muhammad Yasir Zahoor
Keyword(s):  
Missense Mutation ◽  
In Silico Analysis ◽  
Missense Variant ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Mutational Spectrum ◽  
Niemann Pick Disease ◽  
Niemann Pick ◽  
Pick Disease

Objective: Genetic variation analysis of rare autosomal recessive Niemann-Pick disease (NPD) Pakistani patients. Methods: We sequenced the SMPD1 gene including its all coding and flanking regions in seven unrelated sporadic patients suffering from Niemann-Pick disease through targeted exome sequencing. Genetic variants mapping and their protein predictions were evaluated using different bioinformatics tools and clinical phenotypes were correlated. The study was conducted from January 2018 to March 2019 at The Children’s Hospital Lahore. Results: We have mapped five different mutations in SMPD1 gene of enrolled patients with a novel homozygous missense variant (c.1718G>C) (p.Trp573Ser) in one patient. A missense mutation (c.1267C>T) (p.His423Tyr) has been identified in three unrelated patients. A nonsense mutation (c.1327C>T) (p.Arg443Term) and one missense mutation (c.1493G>A) (p.Arg498His) mapped in one patient each. A compound heterozygous mutation has been mapped in one patient (c.740G>A) (p.Gly247Asp); (c.1493G>A) (p.Arg498His). Pathogenic effect of novel variant has been predicted through in-silico analysis and has not been reported in general overall population in the globe. Conclusion: This is the first report of genetic demographic assessment of Niemann-Pick disease in Pakistan. The mapped mutations would be helpful to build a disease variants algorithm of Pakistani population. This will be used for determining disease clinical magnitude along with provision of genetic screening services in affected families. doi: https://doi.org/10.12669/pjms.36.3.467 How to cite this:Cheema HA, Rasool IG, Anjum MN, Zahoor MY. Mutational spectrum of SMPD1 gene in Pakistani Niemann-Pick disease patients. Pak J Med Sci. 2020;36(3):---------. doi: https://doi.org/10.12669/pjms.36.3.467 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Novel compound heterozygous mutation in NPC1 gene cause Niemann–Pick disease type C with juvenile onset

2020 ◽  
Vol 99 (1) ◽  
Author(s):  
Maria Cristina Costanzo ◽  
Antonio Gennaro Nicotera ◽  
Mirella Vinci ◽  
Aurelio Vitello ◽  
Agata Fiumara ◽  
...  
Keyword(s):  
Disease Type ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Juvenile Onset ◽  
Niemann Pick Disease ◽  
Npc1 Gene ◽  
Type C ◽  
Niemann Pick ◽  
Pick Disease

scholarly journals Identification and expression of a common missense mutation (L302P) in the acid sphingomyelinase gene of Ashkenazi Jewish type A Niemann-Pick disease patients

Blood ◽  
1992 ◽  
Vol 80 (8) ◽  
pp. 2081-2087 ◽  
Author(s):  
O Levran ◽  
RJ Desnick ◽  
EH Schuchman
Keyword(s):  
Missense Mutation ◽  
Neurodegenerative Disorder ◽  
Type A ◽  
Acid Sphingomyelinase ◽  
Common Mutation ◽  
Ashkenazi Jewish ◽  
Type B ◽  
Niemann Pick Disease ◽  
Niemann Pick ◽  
Pick Disease

Abstract Types A and B Niemann-Pick disease (NPD) result from the deficient activity of acid sphingomyelinase (ASM; E.C. 3.1.4.12) and the resultant lysosomal accumulation of sphingomyelin. Type A disease is a fatal, neurodegenerative disorder of infancy, whereas type B disease has no neurologic manifestations and is characterized primarily by reticuloendothelial involvement and survival into adulthood. Both disorders occur more frequently among individuals of Ashkenazi Jewish ancestry than in the general population. Recently, a missense mutation in the ASM gene (designated R496L) was detected in more than 30% of the ASM alleles from Ashkenazi Jewish type A NPD patients. We report a second, common mutation that resulted from a T to C transition at nucleotide 905 and predicted a leucine to proline substitution at ASM codon 302 (designated L302P). Notably, the L302P mutation occurred in 23.5% (8 of 34) of the Ashkenazi Jewish type A NPD alleles studied. In contrast, it was not found in any of the ASM alleles from non-Jewish type A patients, in 36 alleles from type B patients, or in 100 ASM alleles from normal Ashkenazi Jewish individuals. To confirm the authenticities of the L302P and R496L mutations, each nucleotide change was separately introduced into the full-length ASM cDNA by site- directed mutagenesis and transiently expressed in COS-1 cells. Neither mutation expressed ASM catalytic activity, consistent with the type A phenotype of homoallelic patients. The identification of the L302P mutation should further facilitate molecular carrier detection for NPD in the Ashkenazi Jewish population, particularly because the L302P mutation can be easily detected using the restriction enzyme, AlwNl.

scholarly journals Compound heterozygous LDLR variant in severely affected familial hypercholesterolemia patient.

1970 ◽  
Vol 64 (1) ◽  
Author(s):  
Faisal A Al-Allaf ◽  
Abdullah Alashwal ◽  
Zainularifeen Abduljaleel ◽  
Mohiuddin M Taher ◽  
Abdellatif Bouazzaoui ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Hepatic Clearance ◽  
Missense Variant ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Tail Domain ◽  
Ldlr Gene ◽  
Arab Population ◽  
Familial Hypercholesterolemia Patient

Familial hypercholesterolemia (FH) is most commonly caused by mutations in the LDL receptor (LDLR), which is responsible for hepatic clearance of LDL from the blood circulation. We described a severely affected FH proband and their first-degree blood relatives; the proband was resistant to statin therapy and was managed on an LDL apheresis program. In order to find the causative genetic variant in this family, direct exon sequencing of the LDLR, APOB and PCSK9 genes was performed. We identified a compound heterozygous mutation in the proband with missense p.(W577C) and frameshift p.(G676Afs33) variants at exons 12 and 14 of the LDLR gene respectively. DNA sequencing of LDLR gene from the parents demonstrated that the missense variant was inherited from the mother and frameshift variant was inherited from the father. The frameshift variant resulted in a stop signal 33 codons downstream of the deletion, which most likely led to a truncated protein that lacks important functional domains, including the trans-membrane domain and the cytoplasmic tail domain. The missense variant is also predicted to be likely pathogenic and affect EGF-precursor homology domain of the LDLR protein. The segregation pattern of the variants was consistent with the lipid profile, suggesting a more severe FH phenotype when the variants are in the compound heterozygous state. The finding of a compound heterozygous mutation causing severe FH phenotype is important for the genotype-phenotype correlation and also enlarges the spectrum of FH-causative LDLR variants in the Arab population, including the Saudi population.

scholarly journals In Silico Analysis of the Molecular-Level Impact of SMPD1 Variants on Niemann-Pick Disease Severity

2021 ◽  
Vol 22 (9) ◽  
pp. 4516
Author(s):  
François Ancien ◽  
Fabrizio Pucci ◽  
Marianne Rooman
Keyword(s):  
Large Scale ◽  
Molecular Level ◽  
In Silico Analysis ◽  
Sphingolipid Metabolism ◽  
Lysosomal Storage ◽  
Niemann Pick Disease ◽  
Niemann Pick ◽  
The Impact ◽  
Pick Disease

Sphingomyelin phosphodiesterase (SMPD1) is a key enzyme in the sphingolipid metabolism. Genetic SMPD1 variants have been related to the Niemann-Pick lysosomal storage disorder, which has different degrees of phenotypic severity ranging from severe symptomatology involving the central nervous system (type A) to milder ones (type B). They have also been linked to neurodegenerative disorders such as Parkinson and Alzheimer. In this paper, we leveraged structural, evolutionary and stability information on SMPD1 to predict and analyze the impact of variants at the molecular level. We developed the SMPD1-ZooM algorithm, which is able to predict with good accuracy whether variants cause Niemann-Pick disease and its phenotypic severity; the predictor is freely available for download. We performed a large-scale analysis of all possible SMPD1 variants, which led us to identify protein regions that are either robust or fragile with respect to amino acid variations, and show the importance of aromatic-involving interactions in SMPD1 function and stability. Our study also revealed a good correlation between SMPD1-ZooM scores and in vitro loss of SMPD1 activity. The understanding of the molecular effects of SMPD1 variants is of crucial importance to improve genetic screening of SMPD1-related disorders and to develop personalized treatments that restore SMPD1 functionality.

Identification and expression of a common missense mutation (L302P) in the acid sphingomyelinase gene of Ashkenazi Jewish type A Niemann-Pick disease patients

Blood ◽  
1992 ◽  
Vol 80 (8) ◽  
pp. 2081-2087
Author(s):  
O Levran ◽  
RJ Desnick ◽  
EH Schuchman
Keyword(s):  
Missense Mutation ◽  
Neurodegenerative Disorder ◽  
Type A ◽  
Acid Sphingomyelinase ◽  
Common Mutation ◽  
Ashkenazi Jewish ◽  
Type B ◽  
Niemann Pick Disease ◽  
Niemann Pick ◽  
Pick Disease

Types A and B Niemann-Pick disease (NPD) result from the deficient activity of acid sphingomyelinase (ASM; E.C. 3.1.4.12) and the resultant lysosomal accumulation of sphingomyelin. Type A disease is a fatal, neurodegenerative disorder of infancy, whereas type B disease has no neurologic manifestations and is characterized primarily by reticuloendothelial involvement and survival into adulthood. Both disorders occur more frequently among individuals of Ashkenazi Jewish ancestry than in the general population. Recently, a missense mutation in the ASM gene (designated R496L) was detected in more than 30% of the ASM alleles from Ashkenazi Jewish type A NPD patients. We report a second, common mutation that resulted from a T to C transition at nucleotide 905 and predicted a leucine to proline substitution at ASM codon 302 (designated L302P). Notably, the L302P mutation occurred in 23.5% (8 of 34) of the Ashkenazi Jewish type A NPD alleles studied. In contrast, it was not found in any of the ASM alleles from non-Jewish type A patients, in 36 alleles from type B patients, or in 100 ASM alleles from normal Ashkenazi Jewish individuals. To confirm the authenticities of the L302P and R496L mutations, each nucleotide change was separately introduced into the full-length ASM cDNA by site- directed mutagenesis and transiently expressed in COS-1 cells. Neither mutation expressed ASM catalytic activity, consistent with the type A phenotype of homoallelic patients. The identification of the L302P mutation should further facilitate molecular carrier detection for NPD in the Ashkenazi Jewish population, particularly because the L302P mutation can be easily detected using the restriction enzyme, AlwNl.

scholarly journals Novel Compound Heterozygous Mutation in TRAPPC9 Gene: The Relevance of Whole Genome Sequencing

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 557
Author(s):  
Maria Isabel Alvarez-Mora ◽  
Jordi Corominas ◽  
Christian Gilissen ◽  
Aurora Sanchez ◽  
Irene Madrigal ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Missense Variant ◽  
Autism Spectrum ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Whole Genome ◽  
Whole Exome ◽  
Considerable Impact

Advances in high-throughput technologies and its implementation worldwide have had a considerable impact on the elucidation of the molecular causes underlying neurodevelopmental psychiatric disorders, especially for autism spectrum disorder and intellectual disability (ID). Nevertheless, etiology remains elusive in close to 50% of cases, even in those families with multiple affected individuals, strongly hinting at a genetic cause. Here we present a case report of two siblings affected with severe ID and other comorbidities, who embarked on a genetic testing odyssey until diagnosis was reached by using whole genome sequencing (WGS). WGS identified a maternally inherited novel missense variant (NM_031466.7:c.1037G > A; p.Gly346Glu) and a paternally inherited 90 kb intragenic deletion in TRAPPC9 gene. This report demonstrates the clinical utility of WGS in patients who remain undiagnosed after whole exome sequencing.

scholarly journals Identification and Expression of a Missense Mutation (Y446C) in the Acid Sphingomyelinase Gene from a Japanese Patient with Type A Niemann-Pick Disease.

1995 ◽  
Vol 177 (2) ◽  
pp. 117-123 ◽  
Author(s):  
TSUTOMU TAKAHASHI ◽  
MARIKO SUCHI ◽  
WATARU SATO ◽  
SVETLANA B. TEN ◽  
NORIO SAKURAGAWA ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Japanese Patient ◽  
Type A ◽  
Acid Sphingomyelinase ◽  
Niemann Pick Disease ◽  
Niemann Pick ◽  
Pick Disease
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