PMID- 10541293
OWN - NLM
STAT- MEDLINE
DCOM- 19991118
LR  - 20210518
IS  - 1046-6673 (Print)
IS  - 1046-6673 (Linking)
VI  - 10
IP  - 11
DP  - 1999 Nov
TI  - Aberrant splicing in the PKD2 gene as a cause of polycystic kidney disease.
PG  - 2342-51
AB  - It is estimated that approximately 15% of families with autosomal dominant
      polycystic kidney disease (ADPKD) have mutations in PKD2. Identification of these
      mutations is central to identifying functionally important regions of gene and to
      understanding the mechanisms underlying the pathogenesis of the disorder. The
      current study describes mutations in six type 2 ADPKD families. Two single base
      substitution mutations discovered in the ORF in exon 14 constitute the most
      COOH-terminal pathogenic variants described to date. One of these mutations is a 
      nonsense change and the other encodes an apparent missense variant. Reverse
      transcription-PCR from patient lymphoblast RNA showed that, in addition, both
      mutations resulted in out-of-frame splice variants by activating cryptic splice
      sites via different mechanisms. The apparent missense variant produced such a
      strong splicing signal that the processed transcript from the mutant chromosome
      did not contain any of the normally spliced, missense product. A third mutation, 
      a nonconservative missense change effecting a negatively charged residue in the
      third transmembrane span, is likely pathogenic and defines a highly conserved
      residue consistent with a potential channel subunit function for polycystin-2.
      The remaining three mutations included two frame shifts resulting from deletion
      of one or two bases in exons 6 and 10, respectively, and a nonsense mutation due 
      to a single base substitution in exon 4. The study also defined a novel
      intragenic polymorphism in exon 1 that will be useful in analyzing "second hits" 
      in PKD2. Finally, the study demonstrates that there are reduced levels of normal 
      polycystin-2 protein in lymphoblast lines from PKD2-affected individuals and that
      truncated mutant polycystin-2 cannot be detected in patient lymphoblasts,
      suggesting that the latter may be unstable in at least some tissues. The
      mutations described will serve as critical reagents for future functional studies
      in PKD2.
FAU - Reynolds, D M
AU  - Reynolds DM
AD  - Department of Medicine, Albert Einstein College of Medicine, Bronx, New York,
      USA.
FAU - Hayashi, T
AU  - Hayashi T
FAU - Cai, Y
AU  - Cai Y
FAU - Veldhuisen, B
AU  - Veldhuisen B
FAU - Watnick, T J
AU  - Watnick TJ
FAU - Lens, X M
AU  - Lens XM
FAU - Mochizuki, T
AU  - Mochizuki T
FAU - Qian, F
AU  - Qian F
FAU - Maeda, Y
AU  - Maeda Y
FAU - Li, L
AU  - Li L
FAU - Fossdal, R
AU  - Fossdal R
FAU - Coto, E
AU  - Coto E
FAU - Wu, G
AU  - Wu G
FAU - Breuning, M H
AU  - Breuning MH
FAU - Germino, G G
AU  - Germino GG
FAU - Peters, D J
AU  - Peters DJ
FAU - Somlo, S
AU  - Somlo S
LA  - eng
GR  - R01DK48383/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Am Soc Nephrol
JT  - Journal of the American Society of Nephrology : JASN
JID - 9013836
RN  - 0 (Membrane Proteins)
RN  - 0 (TRPP Cation Channels)
RN  - 0 (polycystic kidney disease 2 protein)
SB  - IM
MH  - Humans
MH  - Membrane Proteins/*genetics
MH  - *Mutation
MH  - Polycystic Kidney, Autosomal Dominant/*genetics
MH  - Polymorphism, Genetic
MH  - *RNA Splicing
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - TRPP Cation Channels
EDAT- 1999/11/30 00:00
MHDA- 1999/11/30 00:01
CRDT- 1999/11/30 00:00
PHST- 1999/11/30 00:00 [pubmed]
PHST- 1999/11/30 00:01 [medline]
PHST- 1999/11/30 00:00 [entrez]
AID - 10.1681/ASN.V10112342 [doi]
PST - ppublish
SO  - J Am Soc Nephrol. 1999 Nov;10(11):2342-51. doi: 10.1681/ASN.V10112342.