PMID- 10556299
OWN - NLM
STAT- MEDLINE
DCOM- 20000124
LR  - 20190513
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 8
IP  - 13
DP  - 1999 Dec
TI  - Severity of phenotype in cystinosis varies with mutations in the CTNS gene:
      predicted effect on the model of cystinosin.
PG  - 2507-14
AB  - Infantile nephropathic cystinosis is a rare, autosomal recessive disease caused
      by a defect in the transport of cystine across the lysosomal membrane and
      characterized by early onset of renal proximal tubular dysfunction. Late-onset
      cystinosis, a rarer form of the disorder, is characterized by onset of symptoms
      between 12 and 15 years of age. We previously characterized the cystinosis gene, 
      CTNS, and identified pathogenic mutations in patients with infantile nephropathic
      cystinosis, including a common, approximately 65 kb deletion which encompasses
      exons 1-10. Structure predictions suggested that the gene product, cystinosin, is
      a novel integral lysosomal membrane protein. We now examine the predicted effect 
      of mutations on this model of cystinosin. In this study, we screened patients
      with infantile nephropathic cystinosis, those with late-onset cystinosis and
      patients whose phenotype does not fit the classical definitions. We found 23
      different mutations in CTNS; 14 are novel mutations. Out of 25 patients with
      infantile nephropathic cystinosis, 12 have two severely truncating mutations,
      which is consistent with a loss of functional protein, and 13 have missense or
      in-frame deletions, which would result in disruption of transmembrane domains and
      loss of protein function. Mutations found in two late-onset patients affect
      functionally unimportant regions of cystinosin, which accounts for their milder
      phenotype. For three patients, the age of onset of cystinosis was <7 years but
      the course of the disease was milder than the infantile nephropathic form. This
      suggests that the missense mutations found in these individuals allow production 
      of functional protein and may also indicate regions of cystinosin which are not
      functionally important.
FAU - Attard, M
AU  - Attard M
AD  - Nephrourology Unit, Institute of Child Health, University College London Medical 
      School, 30 Guilford Street, London WC1N 1EH, UK.
FAU - Jean, G
AU  - Jean G
FAU - Forestier, L
AU  - Forestier L
FAU - Cherqui, S
AU  - Cherqui S
FAU - van't Hoff, W
AU  - van't Hoff W
FAU - Broyer, M
AU  - Broyer M
FAU - Antignac, C
AU  - Antignac C
FAU - Town, M
AU  - Town M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Amino Acid Transport Systems, Neutral)
RN  - 0 (CTNS protein, human)
RN  - 0 (Glycoproteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (Membrane Transport Proteins)
RN  - 0 (RNA, Messenger)
SB  - IM
MH  - Age of Onset
MH  - Amino Acid Transport Systems, Neutral
MH  - Cystinosis/*genetics
MH  - DNA Mutational Analysis
MH  - Exons
MH  - *Glycoproteins
MH  - Haplotypes
MH  - Humans
MH  - Membrane Proteins/*genetics
MH  - Membrane Transport Proteins
MH  - Microsatellite Repeats
MH  - Models, Molecular
MH  - Phenotype
MH  - Point Mutation
MH  - Polymorphism, Single-Stranded Conformational
MH  - RNA, Messenger/analysis
MH  - Reverse Transcriptase Polymerase Chain Reaction
EDAT- 1999/11/11 00:00
MHDA- 1999/11/11 00:01
CRDT- 1999/11/11 00:00
PHST- 1999/11/11 00:00 [pubmed]
PHST- 1999/11/11 00:01 [medline]
PHST- 1999/11/11 00:00 [entrez]
AID - ddc277 [pii]
AID - 10.1093/hmg/8.13.2507 [doi]
PST - ppublish
SO  - Hum Mol Genet. 1999 Dec;8(13):2507-14. doi: 10.1093/hmg/8.13.2507.