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A donor splice site mutation in CISD2 generates multiple truncated, non-functional isoforms in Wolfram syndrome type 2 patients.

Abstract Mutations in the gene that encodes CDGSH iron sulfur domain 2 (CISD2) are causative of Wolfram syndrome type 2 (WFS2), a rare autosomal recessive neurodegenerative disorder mainly characterized by diabetes mellitus, optic atrophy, peptic ulcer bleeding and defective platelet aggregation. Four mutations in the CISD2 gene have been reported. Among these mutations, the homozygous c.103 + 1G > A substitution was identified in the donor splice site of intron 1 in two Italian sisters and was predicted to cause a exon 1 to be skipped.
PMID
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Authors

Mayor MeshTerms

Mutation

Keywords

CISD2

Non functional isoforms

Nonsense-mediated mRNA decay

Wolfram syndrome type 2

mRNA splicing

Journal Title bmc medical genetics
Publication Year Start




PMID- 29237418
OWN - NLM
STAT- MEDLINE
DCOM- 20171219
LR  - 20171220
IS  - 1471-2350 (Electronic)
IS  - 1471-2350 (Linking)
VI  - 18
IP  - 1
DP  - 2017 Dec 13
TI  - A donor splice site mutation in CISD2 generates multiple truncated,
      non-functional isoforms in Wolfram syndrome type 2 patients.
PG  - 147
LID - 10.1186/s12881-017-0508-2 [doi]
AB  - BACKGROUND: Mutations in the gene that encodes CDGSH iron sulfur domain 2 (CISD2)
      are causative of Wolfram syndrome type 2 (WFS2), a rare autosomal recessive
      neurodegenerative disorder mainly characterized by diabetes mellitus, optic
      atrophy, peptic ulcer bleeding and defective platelet aggregation. Four mutations
      in the CISD2 gene have been reported. Among these mutations, the homozygous c.103
      + 1G > A substitution was identified in the donor splice site of intron 1 in two 
      Italian sisters and was predicted to cause a exon 1 to be skipped. METHODS: Here,
      we employed molecular assays to characterize the c.103 + 1G > A mutation using
      the patient's peripheral blood mononuclear cells (PBMCs). 5'-RACE coupled with
      RT-PCR were used to analyse the effect of the c.103 + 1G > A mutation on mRNA
      splicing. Western blot analysis was used to analyse the consequences of the CISD2
      mutation on the encoded protein. RESULTS: We demonstrated that the c.103 + 1G > A
      mutation functionally impaired mRNA splicing, producing multiple splice variants 
      characterized by the whole or partial absence of exon 1, which introduced amino
      acid changes and a premature stop. The affected mRNAs resulted in either
      predicted targets for nonsense mRNA decay (NMD) or non-functional isoforms.
      CONCLUSIONS: We concluded that the c.103 + 1G > A mutation resulted in the loss
      of functional CISD2 protein in the two Italian WFS2 patients.
FAU - Cattaneo, Monica
AU  - Cattaneo M
AUID- ORCID: http://orcid.org/0000-0002-1866-5866
AD  - Cardiovascular Research Unit, IRCCS MultiMedica, Via G. Fantoli 16/15, 20138,
      Milan, Italy. [email protected]
FAU - La Sala, Lucia
AU  - La Sala L
AD  - Cardiovascular Research Unit, IRCCS MultiMedica, Via G. Fantoli 16/15, 20138,
      Milan, Italy.
FAU - Rondinelli, Maurizio
AU  - Rondinelli M
AD  - Diabetes Endocrine and Metabolic Diseases Unit, IRCCS MultiMedica, 20099 Sesto
      San Giovanni, Milan, Italy.
AD  - IRCCS Centro Cardiologico Monzino Diabetes, Endocrine and Metabolic Diseases
      Unit, 20138, Milan, Italy.
FAU - Errichiello, Edoardo
AU  - Errichiello E
AD  - Department of Molecular Medicine, University of Pavia, 27100, Pavia, Italy.
FAU - Zuffardi, Orsetta
AU  - Zuffardi O
AD  - Department of Molecular Medicine, University of Pavia, 27100, Pavia, Italy.
FAU - Puca, Annibale Alessandro
AU  - Puca AA
AD  - Cardiovascular Research Unit, IRCCS MultiMedica, Via G. Fantoli 16/15, 20138,
      Milan, Italy.
AD  - Department of Medicine and Surgery, University of Salerno, 84084, Salerno, Italy.
FAU - Genovese, Stefano
AU  - Genovese S
AD  - Diabetes Endocrine and Metabolic Diseases Unit, IRCCS MultiMedica, 20099 Sesto
      San Giovanni, Milan, Italy.
AD  - IRCCS Centro Cardiologico Monzino Diabetes, Endocrine and Metabolic Diseases
      Unit, 20138, Milan, Italy.
FAU - Ceriello, Antonio
AU  - Ceriello A
AD  - Cardiovascular Research Unit, IRCCS MultiMedica, Via G. Fantoli 16/15, 20138,
      Milan, Italy.
AD  - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS) and Centro de 
      Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas
      (CIBERDEM), Barcelona, Spain.
LA  - eng
GR  - RF-2011-02348194/Ministero della Salute/United States
PT  - Journal Article
DEP - 20171213
PL  - England
TA  - BMC Med Genet
JT  - BMC medical genetics
JID - 100968552
RN  - 0 (Codon, Nonsense)
RN  - 0 (ERIS protein, human)
RN  - 0 (Membrane Proteins)
RN  - 0 (Protein Isoforms)
RN  - 0 (RNA Splice Sites)
RN  - 0 (RNA, Messenger)
RN  - Wolfram Syndrome 2
SB  - IM
MH  - Aging, Premature/*genetics
MH  - Base Sequence
MH  - Blood Cells
MH  - Codon, Nonsense
MH  - Exons/genetics
MH  - Female
MH  - Hearing Loss, Sensorineural/*genetics
MH  - Humans
MH  - Introns/genetics
MH  - Leukocytes, Mononuclear
MH  - Membrane Proteins/chemistry/*genetics
MH  - Mitochondrial Diseases/*genetics
MH  - *Mutation
MH  - Optic Atrophy/*genetics
MH  - Protein Isoforms/genetics
MH  - RNA Splice Sites/*genetics/physiology
MH  - RNA Splicing
MH  - RNA, Messenger/genetics
MH  - Sequence Analysis
MH  - Sequence Deletion
PMC - PMC5729406
OTO - NOTNLM
OT  - CISD2
OT  - Non functional isoforms
OT  - Nonsense-mediated mRNA decay
OT  - Wolfram syndrome type 2
OT  - mRNA splicing
EDAT- 2017/12/15 06:00
MHDA- 2017/12/20 06:00
CRDT- 2017/12/15 06:00
PHST- 2017/06/14 00:00 [received]
PHST- 2017/11/29 00:00 [accepted]
PHST- 2017/12/15 06:00 [entrez]
PHST- 2017/12/15 06:00 [pubmed]
PHST- 2017/12/20 06:00 [medline]
AID - 10.1186/s12881-017-0508-2 [doi]
AID - 10.1186/s12881-017-0508-2 [pii]
PST - epublish
SO  - BMC Med Genet. 2017 Dec 13;18(1):147. doi: 10.1186/s12881-017-0508-2.