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[Mutation analysis of FAH gene in patients with tyrosinemia type 1].
Zhonghua Er Ke Za Zhi 2013; 51(4):302-7ZE

Abstract

OBJECTIVE

To investigate the clinical features and mutations of the FAH gene.

METHOD

Clinical records of two cases were collected, and diagnosis was made according to the diagnostic criteria of the International Organization for Rare Disorders (NORD). Genomic DNA was extracted from peripheral blood leukocytes with QIAamp DNA Mini Kit. The DNA extracts were subjected to direct sequencing for 14 exons together with adjacent fragments of FAH gene using ABI Prism 3730 Genetic Analyzer (Applied Biosystems, Foster City, CA) after PCR based on genomic DNA. The mutation source was verified by analyzing parents' exons corresponding to patients' mutation exons. The homology between human FAH enzyme and that of other species was surveyed using software Clustal X(European Bioinformatics Institute, Hinxton, Saffron Walde, UK). Polyphen (Polymorphism Phenotyping), available online, were used to predict possible impact of an amino acid substitution on structure and function of FAH enzyme. Polyphen calculates position-specific independent counts (PISC) scores for two amino acid variants in polymorphic position. A PISC scores that differ by > 2 were regarded as indicating the probability of damaging variants.

RESULT

Patient 1 was a 5 months and 21 days-old boy who suffered from persistent diarrhea, hepatomegaly, ascites; Alpha-fetoprotein > 1210 µg/L, levels of tyrosine in blood and succinylacetone in urine were 110.8 µmol/L and 83.7 µmol/L. His sister suffered from tyrosinemia type 1. Direct sequencing showed a G to A transition in CDS position 455 and 1027. He was compound heterozygous for the mutation c.455G > A/c.1027G > A, which predicts a change from tryptophan to a stop codon (TGG > TAG) at position 152 (W152X) and a change from glycine to arginine (GGG > AGG) at position 343 respectively. Patient 2 was a 6 year and 1 month-old girl with late-onset rickets who had signs of hepatosplenomegaly, rachitic rosary, windswept knees. Hypophosphatemia and alkaline phosphatase 1620 IU/L were detected. Alpha-fetoprotein 412.8 µg/L, levels of tyrosine in blood and succinylacetone in urine were 835.8 µmol/L and 27.48 µmol/L. Rickets did not improve after administration of calcium and vitamine D3. She is homozygous for the mutation c.1027G > A/c.1027G > A, which predicts G343R. The parents were mutation carriers. Analysis by Clustal X on the alignment of amino acids residual reservation among different species showed that the locative amino acid was highly conserved. Polyphen software predicted G343R was probably damaging (PISC score 3.235).

CONCLUSION

Children with tyrosinemia type 1 can have manifestations of persistent diarrhea or late-onset rickets. Physical examination can reveal hepatosplenomegaly, laboratory tests indicate markedly elevated serum concentration of alpha-fetoprotein and alkaline phosphatase in plasma and succinylacetone in urine, other members in family may have tyrosinemias or parents are consanguineous. Mutations c.455G > A and c.1027G > A can be detected in FAH gene of Chinese children.

Authors+Show Affiliations

Department of Infectious Diseases, Childrens' Hospital of Fudan University, Shanghai 201102, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

English Abstract
Journal Article
Research Support, Non-U.S. Gov't

Language

chi

PubMed ID

23927806

Citation

Dou, Li-Min, et al. "[Mutation Analysis of FAH Gene in Patients With Tyrosinemia Type 1]." Zhonghua Er Ke Za Zhi = Chinese Journal of Pediatrics, vol. 51, no. 4, 2013, pp. 302-7.
Dou LM, Fang LJ, Wang XH, et al. [Mutation analysis of FAH gene in patients with tyrosinemia type 1]. Zhonghua Er Ke Za Zhi. 2013;51(4):302-7.
Dou, L. M., Fang, L. J., Wang, X. H., Lu, W., Chen, R., Li, L. T., ... Wang, J. S. (2013). [Mutation analysis of FAH gene in patients with tyrosinemia type 1]. Zhonghua Er Ke Za Zhi = Chinese Journal of Pediatrics, 51(4), pp. 302-7.
Dou LM, et al. [Mutation Analysis of FAH Gene in Patients With Tyrosinemia Type 1]. Zhonghua Er Ke Za Zhi. 2013;51(4):302-7. PubMed PMID: 23927806.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - [Mutation analysis of FAH gene in patients with tyrosinemia type 1]. AU - Dou,Li-Min, AU - Fang,Ling-Juan, AU - Wang,Xiao-Hong, AU - Lu,Wei, AU - Chen,Rui, AU - Li,Li-Ting, AU - Zhao,Jing, AU - Wang,Jian-She, PY - 2013/8/10/entrez PY - 2013/8/10/pubmed PY - 2014/1/31/medline SP - 302 EP - 7 JF - Zhonghua er ke za zhi = Chinese journal of pediatrics JO - Zhonghua Er Ke Za Zhi VL - 51 IS - 4 N2 - OBJECTIVE: To investigate the clinical features and mutations of the FAH gene. METHOD: Clinical records of two cases were collected, and diagnosis was made according to the diagnostic criteria of the International Organization for Rare Disorders (NORD). Genomic DNA was extracted from peripheral blood leukocytes with QIAamp DNA Mini Kit. The DNA extracts were subjected to direct sequencing for 14 exons together with adjacent fragments of FAH gene using ABI Prism 3730 Genetic Analyzer (Applied Biosystems, Foster City, CA) after PCR based on genomic DNA. The mutation source was verified by analyzing parents' exons corresponding to patients' mutation exons. The homology between human FAH enzyme and that of other species was surveyed using software Clustal X(European Bioinformatics Institute, Hinxton, Saffron Walde, UK). Polyphen (Polymorphism Phenotyping), available online, were used to predict possible impact of an amino acid substitution on structure and function of FAH enzyme. Polyphen calculates position-specific independent counts (PISC) scores for two amino acid variants in polymorphic position. A PISC scores that differ by > 2 were regarded as indicating the probability of damaging variants. RESULT: Patient 1 was a 5 months and 21 days-old boy who suffered from persistent diarrhea, hepatomegaly, ascites; Alpha-fetoprotein > 1210 µg/L, levels of tyrosine in blood and succinylacetone in urine were 110.8 µmol/L and 83.7 µmol/L. His sister suffered from tyrosinemia type 1. Direct sequencing showed a G to A transition in CDS position 455 and 1027. He was compound heterozygous for the mutation c.455G > A/c.1027G > A, which predicts a change from tryptophan to a stop codon (TGG > TAG) at position 152 (W152X) and a change from glycine to arginine (GGG > AGG) at position 343 respectively. Patient 2 was a 6 year and 1 month-old girl with late-onset rickets who had signs of hepatosplenomegaly, rachitic rosary, windswept knees. Hypophosphatemia and alkaline phosphatase 1620 IU/L were detected. Alpha-fetoprotein 412.8 µg/L, levels of tyrosine in blood and succinylacetone in urine were 835.8 µmol/L and 27.48 µmol/L. Rickets did not improve after administration of calcium and vitamine D3. She is homozygous for the mutation c.1027G > A/c.1027G > A, which predicts G343R. The parents were mutation carriers. Analysis by Clustal X on the alignment of amino acids residual reservation among different species showed that the locative amino acid was highly conserved. Polyphen software predicted G343R was probably damaging (PISC score 3.235). CONCLUSION: Children with tyrosinemia type 1 can have manifestations of persistent diarrhea or late-onset rickets. Physical examination can reveal hepatosplenomegaly, laboratory tests indicate markedly elevated serum concentration of alpha-fetoprotein and alkaline phosphatase in plasma and succinylacetone in urine, other members in family may have tyrosinemias or parents are consanguineous. Mutations c.455G > A and c.1027G > A can be detected in FAH gene of Chinese children. SN - 0578-1310 UR - https://www.unboundmedicine.com/medline/citation/23927806/[Mutation_analysis_of_FAH_gene_in_patients_with_tyrosinemia_type_1]_ L2 - http://journal.yiigle.com/LinkIn.do?linkin_type=pubmed&issn=0578-1310&year=2013&vol=51&issue=4&fpage=302 DB - PRIME DP - Unbound Medicine ER -