Linkage disequilibrium mapping of the Nova Scotia variant of Niemann–Pick disease

Greer, W.L.; Riddell, D. Christie; Murty, Surya; Gillan, T.L.; Girouard, GS; Sparrow, SM; Tatlidil, C; Dobson, Melanie J.; Neumann, PE

doi:10.1034/j.1399-0004.1999.550406.x

Cited by 13 publications

(5 citation statements)

References 12 publications

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“…Since identification of the NPC1 gene, a number of studies have been conducted to characterize the various genetic mutations and to correlate mutations with the biochemical and clinical phenotype [Greer et al, 1999a,b; Meiner et al, 2001; Tarugi et al, 2002]. To date, approximately 200 different genetic mutations and 60 different polymorphisms have been identified for the NPC1 gene [Park et al, 2003; Scott and Ioannou, 2004; Fernandez‐Valero et al, 2005].…”

Section: Introductionmentioning

confidence: 99%

The National Niemann–Pick C1 disease database: Report of clinical features and health problems

Garver¹,

Francis²,

Jelínek³

et al. 2007

American J of Med Genetics Pt A

154

130

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Niemann-Pick type C1 (NPC1) disease is an autosomal recessive disorder characterized clinically by neonatal jaundice, hepatosplenomegaly, vertical gaze palsy, ataxia, dystonia, and progressive neurodegeneration. The present study provides basic clinical and health information from the National Niemann-Pick C1 disease database that was obtained using a clinical questionnaire of 83 questions mailed to families affected by NPC1 disease living in the United States. The study was conducted over a 1-year period, during which time parents/caregivers and physicians completed the clinical questionnaire. Sixty-four percent (87/136) of the questionnaires were returned, with 53% and 47% representing male and female NPC1 patients, respectively. The average age of diagnosis for NPC1 disease was 10.4 years, with one-half of patients being diagnosed before the age of 6.9 years. The average age of death for NPC1 disease was 16.2 years, with one-half of patients dying before the age of 12.5 years. A common clinical symptom reported at birth was neonatal jaundice (52%), followed by enlargement of the spleen (36%) and liver (31%); ascites (19%) and neonatal hypotonia (6%) were much less frequent. With respect to developmental difficulties, the most common findings included clumsiness (87%), learning difficulties (87%), ataxia (83%), dysphagia (80%), and vertical gaze palsy (81%). Together, these findings confirm and extend previous reports investigating the clinical features associated with NPC1 disease.

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Section: Introductionmentioning

confidence: 99%

The National Niemann–Pick C1 disease database: Report of clinical features and health problems

Garver¹,

Francis²,

Jelínek³

et al. 2007

American J of Med Genetics Pt A

154

130

View full text Add to dashboard Cite

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“…Traditionally, Niemann-Pick type II disease has been divided into two entities: type C (NPC [MIM 257220]) and type D (NPD [MIM 257250]). NPD, the Nova Scotia variant, was distinguished by its less severe phenotype and by the Acadian ancestry of affected individuals (Winsor and Welch 1978;Greer et al 1999).…”

Section: Introductionmentioning

confidence: 99%

Mutations in NPC1 Highlight a Conserved NPC1-Specific Cysteine-Rich Domain

Greer

Dobson

Girouard

et al. 1999

The American Journal of Human Genetics

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104

108

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Niemann-Pick type II disease is an autosomal recessive disorder characterized by a defect in intracellular trafficking of sterols. We have determined the intron/exon boundaries of eight exons from the conserved 3' portion of NPC1, the gene associated with most cases of the disease. SSCP analyses were designed for these exons and were used to identify the majority of mutations in 13 apparently unrelated families. Thirteen mutations were found, accounting for 19 of the 26 alleles. These mutations included eight different missense mutations (including one reported by Greer et al. [1998]), one 4-bp and two 2-bp deletions that generate premature stop codons, and two intronic mutations that are predicted to alter splicing. Two of the missense mutations were present in predicted transmembrane (TM) domains. Clustering of these and other reported NPC1 mutations in the carboxy-terminal third of the protein indicates that screening of these exons, by means of the SSCP analyses reported here, will detect most mutations. The carboxy-terminal half of the Npc1 protein shares amino acid similarity with the TM domains of the morphogen receptor Patched, with the largest stretch of unrelated sequence lying between two putative TM spans. Alignment of this portion of the human Npc1 protein sequence with Npc1-related sequences from mouse, yeast, nematode, and a plant, Arabidopsis, revealed conserved cysteine residues that may coordinate the structure of this domain. That 7 of a total of 13 NPC1 missense mutations are concentrated in this single Npc1-specific domain suggests that integrity of this region is particularly critical for normal functioning of the protein.

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“…Since the identifi cation of the NPC1 gene, a number of studies have characterized various mutations and attempted to associate these mutations with a biochemical and clinical phenotype (26)(27)(28)(29). To date, more than 243 different loss-of-function mutations of NPC1 have been reported ( 30,31 ), in addition to 60 different nondiseasecausing polymorphisms (31)(32)(33)(34).…”

Section: Npc1 Lipid Profi Les and Gene Mutationsmentioning

confidence: 99%

The National Niemann-Pick Type C1 Disease Database: correlation of lipid profiles, mutations, and biochemical phenotypes

Garver

Jelínek

Meaney

et al. 2010

Journal of Lipid Research

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Niemann-Pick type C1 disease (NPC1) is an autosomal recessive lipid storage disorder characterized by clinical manifestations involving primarily the liver and brain ( 1 ). The onset of signs or symptoms can occur at any age and have a variable phenotype. The classic clinical phenotype is also variable and includes mid-to-late childhood onset of gait disturbance followed by progressive neurodegeneration with vertical gaze palsy, seizures, and dementia, resulting in death during the second or third decade ( 2-4 ). The clinical phenotype of NPC1 disease has been categorized according to the age of onset of symptoms ( 5, 6 ), including an early-onset, rapidly progressive form associated with hepatic dysfunction and psychomotor delay during infancy, the classic form, and a late-onset type characterized by a slowly progressive intellectual impairment in adolescence or adulthood.The gene responsible for NPC1 disease, NPC1 , was localized to chromosome 18 using linkage analysis and subsequently identifi ed using positional mapping and Abstract Niemann-Pick type C1 disease (NPC1) is an autosomal recessive lysosomal storage disorder characterized by neonatal jaundice, hepatosplenomegaly, and progressive neurodegeneration. The present study provides the lipid profi les, mutations, and corresponding associations with the biochemical phenotype obtained from NPC1 patients who participated in the National NPC1 Disease Database. Lipid profi les were obtained from 34 patients (39%) in the survey and demonstrated signifi cantly reduced plasma LDL cholesterol (LDL-C) and increased plasma triglycerides in the majority of patients. Reduced plasma HDL cholesterol (HDL-C) was the most consistent lipoprotein abnormality found in male and female NPC1 patients across age groups and occurred independent of changes in plasma triglycerides. A subset of 19 patients for whom the biochemical severity of known NPC1 mutations could be correlated with their lipid profi le showed a strong inverse correlation between plasma HDL-C and severity of the biochemical phenotype. Gene mutations were available for 52 patients (59%) in the survey, including 52 different mutations and fi ve novel mutations (Y628C, P887L, I923V, A1151T, and 3741_ 3744delACTC). Together, these fi ndings provide novel information regarding the plasma lipoprotein changes and mutations in NPC1 disease, and suggest plasma HDL-C represents a potential biomarker of NPC1 disease severity. -Garver, W.

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Linkage disequilibrium mapping of the Nova Scotia variant of Niemann–Pick disease

Cited by 13 publications

References 12 publications

The National Niemann–Pick C1 disease database: Report of clinical features and health problems

The National Niemann–Pick C1 disease database: Report of clinical features and health problems

Mutations in NPC1 Highlight a Conserved NPC1-Specific Cysteine-Rich Domain

The National Niemann-Pick Type C1 Disease Database: correlation of lipid profiles, mutations, and biochemical phenotypes

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