title: Novel mutations in Indian patients with autosomal recessive infantile malignant osteopetrosis.
abstract: OBJECTIVE
  Although clinical reports have described infantile malignant autosomal recessive osteopetrosis (ARO) in Indian patients, no published data are available about the genetic causes of ARO in this population. We investigated the main genetic causes of ARO in eight Indian patients with early postnatal onset and the typical severe clinical course including visual impairment and anaemia.
  
  
  METHODS
  Mutation screening in the genes CLCN7 and TCIRG1 was done on genomic DNA from 8 affected individuals (diagnosed on the basis of clinical and haematological parameters and characteristic radiological changes of increased bone density) and their parents. In one family, after detection of both mutations in the proband, targeted mutation analysis was also done in chorionic villus samples for prenatal diagnosis.
  
  
  RESULTS
  Six patients had mutations in TCIRG1 and two patients harboured mutations in CLCN7 gene. Three of the five different TCIRG1 mutations identified and both CLCN7 mutations were novel mutations. Except for the already known mutation p.Ile720del, all TCIRG1 mutations disrupt conserved splice consensus sequences or lead to premature stop codons. In contrast, both CLCN7 mutations only lead to missense changes of conserved amino acids. In a foetus harbouring TCIRG1 mutations osteopetrosis was visible radiologically at 23 wk of gestation.
  
  
  CONCLUSIONS
  That the CLCN7 mutations provoke a phenotype as severe as the one caused by TCIRG1 loss of function suggests the affected residues to be crucial for the function of the ClC-7 chloride channel or chloride/proton-exchanger. Our data also show that ARO can manifest as early as in the second trimester of pregnancy.
authors.affiliation: Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India. shubha@sgpgi.ac.in
authors.forename: Shubha R
authors.initials: SR
authors.lastname: Phadke
authors.forename: Bjoern
authors.initials: B
authors.lastname: Fischer
authors.forename: Neerja
authors.initials: N
authors.lastname: Gupta
authors.forename: Prajnya
authors.initials: P
authors.lastname: Ranganath
authors.forename: Madhulika
authors.initials: M
authors.lastname: Kabra
authors.forename: Uwe
authors.initials: U
authors.lastname: Kornak
mesh_terms: D018118:Chloride Channels / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D007194:India; D007223:Infant; D008297:Male; D009154:Mutation; D010022:Osteopetrosis / Q000235:genetics*; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics*
chemical_list: C097540:CLCN7 protein, human; D018118:Chloride Channels; C472421:TCIRG1 protein, human; D025262:Vacuolar Proton-Translocating ATPases