title: Homozygosity for TNSALP mutation 1348c>T (Arg433Cys) causes infantile hypophosphatasia manifesting transient disease correction and variably lethal outcome in a kindred of black ancestry.
abstract: OBJECTIVE
  To determine the "tissue-nonspecific" isoenzyme of alkaline phosphatase (TNSALP) defect underlying transiently reversible and variably lethal infantile hypophosphatasia (HPP) in a kindred and to characterize HPP prevalence in black people.
  
  
  METHODS
  In 1986, we reported temporary correction of severe HPP in an American kindred of black ancestry where "infantile" HPP was fatal in 2 of 3 affected individuals representing 2 sibships. This transient improvement in 1 patient followed efforts to increase TNSALP activity endogenously and suggested dysregulation of the gene (TNSALP). Here, we sequenced the coding exons and splice sites of the kindred's TNSALP alleles and reviewed our 30-year experience with HPP to assess its prevalence in black people.
  
  
  RESULTS
  Homozygosity for TNSALP missense mutation 1348C>T (Arg433Cys) accounted for this kindred's infantile HPP. The TNSALP promoter sequence was normal. Modeling of TNSALP(433Cys) suggested compromise of the catalytic site. Ethnicity was identified for the 119 families with HPP studied in St. Louis, and race was ascertained for an additional 159 of our 235 consult and HPP families worldwide. In this experience, only this family was of black ancestry.
  
  
  CONCLUSIONS
  Infantile HPP from homozygous TNSALP(433Cys) can remit and thus harbor clues regarding the phenotypic variation and perhaps treatment of HPP.
authors.affiliation: Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, Missouri 63131, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Whyte
authors.forename: Kevan
authors.initials: K
authors.lastname: Essmyer
authors.forename: Michael
authors.initials: M
authors.lastname: Geimer
authors.forename: Steven
authors.initials: S
authors.lastname: Mumm
mesh_terms: D001741:Black or African American / Q000235:genetics*; D000469:Alkaline Phosphatase / Q000235:genetics*; D001120:Arginine / Q000235:genetics; D002675:Child, Preschool; D003545:Cysteine / Q000235:genetics; D015180:Electrophoresis, Gel, Two-Dimensional; D006720:Homozygote; D006801:Humans; D007014:Hypophosphatasia / Q000453:epidemiology / Q000235:genetics*; D007231:Infant, Newborn; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D015995:Prevalence; D022821:RNA Splice Sites
chemical_list: D007527:Isoenzymes; D022821:RNA Splice Sites; D001120:Arginine; D000469:Alkaline Phosphatase; D003545:Cysteine