title: Direct sequencing of FAH gene in Pakistani tyrosinemia type 1 families reveals a novel mutation.
abstract: BACKGROUND
  Hereditary tyrosinemia type 1 (HT1) is a rare inborn error of tyrosine catabolism with a worldwide prevalence of one out of 100,000 live births. HT1 is clinically characterized by hepatic and renal dysfunction resulting from the deficiency of fumarylacetoacetate hydrolase (FAH) enzyme, caused by recessive mutations in the FAH gene. We present here the first report on identification of FAH mutations in HT1 patients from Pakistan with a novel one.
  
  
  METHODS
  Three Pakistani families, each having one child affected with HT1, were enrolled over a period of 1.5 years. Two of the affected children had died as they were presented late with acute form. All regions of the FAH gene spanning exons and splicing sites were amplified by polymerase chain reaction (PCR) and mutation analysis was carried out by direct sequencing. Results of sequencing were confirmed by restriction fragment length polymorphism (PCR-RFLP) analysis.
  
  
  RESULTS
  Three different FAH mutations, one in each family, were found to co-segregate with the disease phenotype. Two of these FAH mutations have been known (c.192G>T and c.1062+5G>A [IVS12+5G>A]), while c.67T>C (p.Ser23Pro) was a novel mutation. The novel variant was not detected in any of 120 chromosomes from normal ethnically matched individuals.
  
  
  CONCLUSIONS
  Most of the HT1 patients die before they present to hospitals in Pakistan, as is indicated by enrollment of only three families in 1.5 years. Most of those with late clinical presentation do not survive due to delayed diagnosis followed by untimely treatment. This tragic condition advocates the establishment of expanded newborn screening program for HT1 within Pakistan.
authors.forename: Sadaqat
authors.initials: S
authors.lastname: Ijaz
authors.forename: Muhammad Yasir
authors.initials: MY
authors.lastname: Zahoor
authors.forename: Muhammad
authors.initials: M
authors.lastname: Imran
authors.forename: Sibtain
authors.initials: S
authors.lastname: Afzal
authors.forename: Munir A
authors.initials: MA
authors.lastname: Bhinder
authors.forename: Ihsan
authors.initials: I
authors.lastname: Ullah
authors.forename: Huma Arshad
authors.initials: HA
authors.lastname: Cheema
authors.forename: Khushnooda
authors.initials: K
authors.lastname: Ramzan
authors.forename: Wasim
authors.initials: W
authors.lastname: Shehzad
mesh_terms: D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D006801:Humans; D006867:Hydrolases / Q000235:genetics*; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D010154:Pakistan; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011379:Prognosis; D017422:Sequence Analysis, DNA / Q000379:methods*; D020176:Tyrosinemias / Q000175:diagnosis* / Q000235:genetics*
chemical_list: D006867:Hydrolases; C020156:fumarylacetoacetase