ABCMdb

ABCG5 p.Arg446*

ClinVar:

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[hide] Clinical observations, molecular genetic analysis,... J Inherit Metab Dis. 2010 Aug;33(4):437-43. Epub 2010 Jun 3. Niu DM, Chong KW, Hsu JH, Wu TJ, Yu HC, Huang CH, Lo MY, Kwok CF, Kratz LE, Ho LT
Clinical observations, molecular genetic analysis, and treatment of sitosterolemia in infants and children.
J Inherit Metab Dis. 2010 Aug;33(4):437-43. Epub 2010 Jun 3., [PMID:20521169]

Abstract [show]
The clinical observation and treatment of young children with sitosterolemia has rarely been reported. We report clinical, biochemical, and molecular genetic observations and treatment outcomes for five Chinese children from four separate families presenting with sitosterolemia in whom we identified two new (Y329X, G269R) and three known (R446X, N437K, R389H) mutations in the ABCG5 gene. The R389H mutation was found in 50% of alleles. Three of these five patients received cholestyramine therapy with a very good response. However, all patients discontinued this therapy because of poor compliance. Finally, all patients were on ezetimibe therapy and had satisfactory total serum cholesterol levels, though their plant sterol levels were still higher than normal. Another noteworthy finding is that a female infant had a serum cholesterol level of 654 mg/dl at 7 months of age, despite being breast fed (with very tiny amounts of plant sterols) since birth and undergoing 4 months of ezetimibe administration. Although she failed to respond to ezetimibe during this period, she did show improvement when the therapy was started again at 2 years of age. It is possible that another 23-month-old female patient also responded more slowly to ezetimibe treatment than older patients.

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1 We report clinical, biochemical, and molecular genetic observations and treatment outcomes for five Chinese children from four separate families presenting with sitosterolemia in whom we identified two new (Y329X, G269R) and three known (R446X, N437K, R389H) mutations in the ABCG5 gene. Login to comment
23 Large peaks of serum plant sterols were identified by nuclear magnetic resonance (NMR) spectroscopy, but the exact concentrations of these sterols were unable to be Table 1 Baseline lipid profiles, liver enzymes, and blood cell counts of each study patient Patient no Normal values 1 2 3 4 5 Age at diagnosis 8 years 18 months 3 months 23 months 12 years Mutation (ABCG5) Y329X R389H R389H R389H R389H N437K R446X R446X R389H G269R Initial diagnostic data Cholesterol, mg/dl Total 125-240 427 705 402 640 343 Low-density-lipoprotein 60-150 346 565 304 519 263 High-density-lipoprotein 35-84 59 64 42 64 50 Total triglycerides, mg/dl 20-200 111 149 395a 98 98 Liver enzymes Alanine transaminase, U/l 5-45 10 13 45 15 44 Aspartate aminotransferase, U/l 15-55 19 31 100 31 37 Blood count Erythrocytes, count/µl 3.7×109 -5.3×109 3.35×109 4.25×109 3.98×109 4.49×109 4.46×109 Hemoglobin, g/dl 11.5-15.5 9.8 11.8 11 12.7 12.9 Mean corpuscular volume, fl 80-95 88.5 89.0 80.6 80.2 86 White blood cells, count/µl 4,500-17,500 7,200 6,900 6,700 11,200 5,200 Platelets, count/mm3 150×106 -350×106 211×106 289×106 506×106 566×106 293×106 After ezetimibe therapy Age at plant sterols analysis NA 5 years 3 years 3 year 13 year Duration of ezetimibe treatment NA 3 years 1 year 1 year 6 months Cholesterol, total (mg/dl) 125-240 NA 181 208 223 193 Sitosterol mg/dlb 0.216±0.220 (SD)c NA 7.10 9.17 7.07 6.14 Campesterol mg/dlb 0.309±0.165 (SD)c NA 3.79 4.78 4.04 4.22 NA not available a In the nonfasting state b Plant sterols were measured by gas chromatography/mass spectrometry, as previously described (Kwiterovich et al. 2003). Login to comment
79 Patients 2 and 3 also had compound heterozygous mutations (R389H and R446X). Login to comment
82 R446X (c.1336C>T), located at exon 10, substituted an arginine codon for a stop codon at codon 446. Login to comment

[hide] Identification by whole-genome resequencing of gen... Hum Mol Genet. 2010 Nov 15;19(22):4313-8. Epub 2010 Aug 18. Rios J, Stein E, Shendure J, Hobbs HH, Cohen JC
Identification by whole-genome resequencing of gene defect responsible for severe hypercholesterolemia.
Hum Mol Genet. 2010 Nov 15;19(22):4313-8. Epub 2010 Aug 18., 2010-11-15 [PMID:20719861]

Abstract [show]
Whole-genome sequencing is a potentially powerful tool for the diagnosis of genetic diseases. Here, we used sequencing-by-ligation to sequence the genome of an 11-month-old breast-fed girl with xanthomas and very high plasma cholesterol levels (1023 mg/dl). Her parents had normal plasma cholesterol levels and reported no family history of hypercholesterolemia, suggesting either an autosomal recessive disorder or a de novo mutation. Known genetic causes of severe hypercholesterolemia were ruled out by sequencing the responsible genes (LDLRAP, LDLR, PCSK9, APOE and APOB), and sitosterolemia was ruled out by documenting a normal plasma sitosterol:cholesterol ratio. Sequencing revealed 3 797 207 deviations from the reference sequence, of which 9726 were nonsynonymous single-nucleotide substitutions. A total of 9027 of the nonsynonymous substitutions were present in dbSNP or in 21 additional individuals from whom complete exonic sequences were available. The 699 novel nonsynonymous substitutions were distributed among 604 genes, 23 of which were single-copy genes that each contained 2 nonsynonymous substitutions consistent with an autosomal recessive model. One gene, ABCG5, had two nonsense mutations (Q16X and R446X). This finding indicated that the infant has sitosterolemia. Thus, whole-genome sequencing led to the diagnosis of a known disease with an atypical presentation. Diagnosis was confirmed by the finding of severe sitosterolemia in a blood sample obtained after the infant had been weaned. These findings demonstrate that whole-genome (or exome) sequencing can be a valuable aid to diagnose genetic diseases, even in individual patients.

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7 One gene, ABCG5, had two nonsense mutations (Q16X and R446X). Login to comment
65 A single gene, ABCG5, contained two different nonsense mutations: Q16X and R446X (Fig. 2B). Login to comment
66 Sanger sequencing confirmed both mutations in the proband and that her mother and father were heterozygotes for the Q16X and R446X mutations, respectively (data not shown). Login to comment
68 The ABCG5-R446X mutation was observed in a 10-year-old girl with sitosterolemia (21), whereas the Q16X mutation has not been reported previously. Login to comment

[hide] Macrothrombocytopenia/Stomatocytosis specially ass... Clin Appl Thromb Hemost. 2012 Nov;18(6):582-7. doi: 10.1177/1076029611435090. Epub 2012 Jan 31. Wang G, Cao L, Wang Z, Jiang M, Sun X, Bai X, Ruan C
Macrothrombocytopenia/Stomatocytosis specially associated with phytosterolemia.
Clin Appl Thromb Hemost. 2012 Nov;18(6):582-7. doi: 10.1177/1076029611435090. Epub 2012 Jan 31., [PMID:22297561]

Abstract [show]
Phytosterolemia is a rare autosomal recessive disease of plant sterol metabolism, the pathophysiological features of which are high plasma levels of plant sterols and xanthomatosis caused by mutations of ABCG5 and ABCG8 genes, and the combination of hemolysis and macrothrombocytopenia is an unusual clinical manifestation. All the patients of the 3 unrelated phytosterolemia first presented with prominent macrothrombocytopenia and stomatocytosis. They were either homozygous or compound heterozygous for ABCG5/ABCG8 gene mutations and had significantly elevated serum plant sterols levels quantified using high-performance liquid chromatography. The in vitro study demonstrated that sitosterol can cause changes in shape and osmotic fragility of red blood cells. These findings suggest that macrothrombocytopenia and stomatocytosis could be initial and main features in some patients with phytosterolemia and that serum phytosterols and relevant genes should be analyzed in patients whose macrothrombocytopenia and/or stomatocytosis are unexplained, especially whose parents are of consanguineous marriage.

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68 The proband of family A was a homozygote for a C20896T nonsense mutation (R446X) which had been discovered.13 The 4 patients of family C were compound heterozygous for C20896T (R446X) and A20883G. Login to comment
67 The proband of family A was a homozygote for a C20896T nonsense mutation (R446X) which had been discovered.13 The 4 patients of family C were compound heterozygous for C20896T (R446X) and A20883G. Login to comment

[hide] Identification of a novel mutation for phytosterol... Clin Chim Acta. 2009 Mar;401(1-2):165-9. Epub 2008 Nov 5. Togo M, Hashimoto Y, Iso-O N, Kurano M, Hara M, Kadowaki T, Koike K, Tsukamoto K
Identification of a novel mutation for phytosterolemia. Genetic analyses of 2 cases.
Clin Chim Acta. 2009 Mar;401(1-2):165-9. Epub 2008 Nov 5., [PMID:19111681]

Abstract [show]
BACKGROUND: Phytosterolemia is one of the genetic disorders causing hypercholesterolemia and atherosclerosis together with the accumulation of plant sterol in plasma and tissues. The mutations in ABCG5 and ABCG8 genes, encoding sterolin-1 and -2, respectively, are responsible for phytosterolemia. METHODS: We performed genetic analyses on 2 Japanese phytosterolemia patients. RESULTS: We identified 2 mutations in the ABCG5 gene in these patients. The first patient was homozygous for a novel mutation, which was a 19-base pair tandem repeat insertion in exon 7, leading to a premature termination at codon 288. The second patient was a compound heterozygote; one of the mutations was the same as that found in the first patient, while the other mutation was a C to T substitution in exon 10, resulting in a premature termination at codon 446 (R446X). No other mutation was found in the ABCG5 and ABCG8 genes. CONCLUSIONS: This result was concordant with previous observations that found most Asian phytosterolemia patients possessed mutations in the ABCG5 gene, and the site of the novel mutation was completely different from these previous reports, necessitating the extensive analyses for phytosterolemia.

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6 The second patient was a compound heterozygote; one of the mutations was the same as that found in the first patient, while the other mutation was a C to T substitution in exon 10, resulting in a premature termination at codon 446 (R446X). Login to comment