Mutations in the gene DNAJC5 cause autosomal dominant kufs disease in a proportion of cases: Study of the parry family and 8 other families

Milen Velinov, Natalia Dolzhanskaya, Michael Gonzalez, Eric Powell, Ioanna Konidari, William Hulme, John F. Staropoli, Winnie Xin, Guang Y. Wen, Rosemary Barone, Scott H. Coppel, Katherine Sims, W. Ted Brown, Stephan L Zuchner

Research output: Contribution to journalArticle

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Abstract

Background: The Neuronal Ceroid Lipofuscinoses (NCL) comprise at least nine progressive neurodegenerative genetic disorders. Kufs disease, an adult-onset form of NCL may be recessively or dominantly inherited. Our study aimed to identify genetic mutations associated with autosomal dominant Kufs disease (ADKD). Methodology and Principal Findings: We have studied the family first reported with this phenotype in the 1970s, the Parry family. The proband had progressive psychiatric manifestations, seizures and cognitive decline starting in her mid 20 s. Similarly affected relatives were observed in seven generations. Several of the affected individuals had post-mortem neuropathological brain study confirmatory for NCL disease. We conducted whole exome sequencing of three affected family members and identified a pLeu116del mutation in the gene DNAJC5, which segregated with the disease phenotype. An additional eight unrelated affected individuals with documented autosomal dominant or sporadic inheritance were studied. All had diagnostic confirmation with neuropathological studies of brain tissue. Among them we identified an additional individual with a p.Leu115Arg mutation in DNAJC5. In addition, a pAsn477Ser change in the neighboring gene PRPF6, a gene previously found to be associated with retinitis pigmentosa, segregated with the ADKD phenotype. Interestingly, two individuals of the Parry family did report visual impairment. Conclusions: Our study confirmed the recently reported association of DNAJC5 mutations with ADKD in two out of nine well-defined families. Sequence changes in PRPF6 have not been identified in other unrelated cases. The association of vision impairment with the expected PRPF6 dysfunction remains possible but would need further clinical studies in order to confirm the co-segregation of the visual impairment with this sequence change.

Original languageEnglish
Article numbere29729
JournalPLoS One
Volume7
Issue number1
DOIs
StatePublished - Jan 3 2012

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Neuronal Ceroid-Lipofuscinoses
Genes
Ceroid
case studies
mutation
Mutation
phenotype
vision disorders
genes
brain
Vision Disorders
Phenotype
Brain
genetic disorders
seizures
clinical trials
inheritance (genetics)
Exome
Inborn Genetic Diseases
Retinitis Pigmentosa

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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Mutations in the gene DNAJC5 cause autosomal dominant kufs disease in a proportion of cases : Study of the parry family and 8 other families. / Velinov, Milen; Dolzhanskaya, Natalia; Gonzalez, Michael; Powell, Eric; Konidari, Ioanna; Hulme, William; Staropoli, John F.; Xin, Winnie; Wen, Guang Y.; Barone, Rosemary; Coppel, Scott H.; Sims, Katherine; Brown, W. Ted; Zuchner, Stephan L.

In: PLoS One, Vol. 7, No. 1, e29729, 03.01.2012.

Research output: Contribution to journalArticle

Velinov, M, Dolzhanskaya, N, Gonzalez, M, Powell, E, Konidari, I, Hulme, W, Staropoli, JF, Xin, W, Wen, GY, Barone, R, Coppel, SH, Sims, K, Brown, WT & Zuchner, SL 2012, 'Mutations in the gene DNAJC5 cause autosomal dominant kufs disease in a proportion of cases: Study of the parry family and 8 other families', PLoS One, vol. 7, no. 1, e29729. https://doi.org/10.1371/journal.pone.0029729
Velinov, Milen ; Dolzhanskaya, Natalia ; Gonzalez, Michael ; Powell, Eric ; Konidari, Ioanna ; Hulme, William ; Staropoli, John F. ; Xin, Winnie ; Wen, Guang Y. ; Barone, Rosemary ; Coppel, Scott H. ; Sims, Katherine ; Brown, W. Ted ; Zuchner, Stephan L. / Mutations in the gene DNAJC5 cause autosomal dominant kufs disease in a proportion of cases : Study of the parry family and 8 other families. In: PLoS One. 2012 ; Vol. 7, No. 1.
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abstract = "Background: The Neuronal Ceroid Lipofuscinoses (NCL) comprise at least nine progressive neurodegenerative genetic disorders. Kufs disease, an adult-onset form of NCL may be recessively or dominantly inherited. Our study aimed to identify genetic mutations associated with autosomal dominant Kufs disease (ADKD). Methodology and Principal Findings: We have studied the family first reported with this phenotype in the 1970s, the Parry family. The proband had progressive psychiatric manifestations, seizures and cognitive decline starting in her mid 20 s. Similarly affected relatives were observed in seven generations. Several of the affected individuals had post-mortem neuropathological brain study confirmatory for NCL disease. We conducted whole exome sequencing of three affected family members and identified a pLeu116del mutation in the gene DNAJC5, which segregated with the disease phenotype. An additional eight unrelated affected individuals with documented autosomal dominant or sporadic inheritance were studied. All had diagnostic confirmation with neuropathological studies of brain tissue. Among them we identified an additional individual with a p.Leu115Arg mutation in DNAJC5. In addition, a pAsn477Ser change in the neighboring gene PRPF6, a gene previously found to be associated with retinitis pigmentosa, segregated with the ADKD phenotype. Interestingly, two individuals of the Parry family did report visual impairment. Conclusions: Our study confirmed the recently reported association of DNAJC5 mutations with ADKD in two out of nine well-defined families. Sequence changes in PRPF6 have not been identified in other unrelated cases. The association of vision impairment with the expected PRPF6 dysfunction remains possible but would need further clinical studies in order to confirm the co-segregation of the visual impairment with this sequence change.",
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N2 - Background: The Neuronal Ceroid Lipofuscinoses (NCL) comprise at least nine progressive neurodegenerative genetic disorders. Kufs disease, an adult-onset form of NCL may be recessively or dominantly inherited. Our study aimed to identify genetic mutations associated with autosomal dominant Kufs disease (ADKD). Methodology and Principal Findings: We have studied the family first reported with this phenotype in the 1970s, the Parry family. The proband had progressive psychiatric manifestations, seizures and cognitive decline starting in her mid 20 s. Similarly affected relatives were observed in seven generations. Several of the affected individuals had post-mortem neuropathological brain study confirmatory for NCL disease. We conducted whole exome sequencing of three affected family members and identified a pLeu116del mutation in the gene DNAJC5, which segregated with the disease phenotype. An additional eight unrelated affected individuals with documented autosomal dominant or sporadic inheritance were studied. All had diagnostic confirmation with neuropathological studies of brain tissue. Among them we identified an additional individual with a p.Leu115Arg mutation in DNAJC5. In addition, a pAsn477Ser change in the neighboring gene PRPF6, a gene previously found to be associated with retinitis pigmentosa, segregated with the ADKD phenotype. Interestingly, two individuals of the Parry family did report visual impairment. Conclusions: Our study confirmed the recently reported association of DNAJC5 mutations with ADKD in two out of nine well-defined families. Sequence changes in PRPF6 have not been identified in other unrelated cases. The association of vision impairment with the expected PRPF6 dysfunction remains possible but would need further clinical studies in order to confirm the co-segregation of the visual impairment with this sequence change.

AB - Background: The Neuronal Ceroid Lipofuscinoses (NCL) comprise at least nine progressive neurodegenerative genetic disorders. Kufs disease, an adult-onset form of NCL may be recessively or dominantly inherited. Our study aimed to identify genetic mutations associated with autosomal dominant Kufs disease (ADKD). Methodology and Principal Findings: We have studied the family first reported with this phenotype in the 1970s, the Parry family. The proband had progressive psychiatric manifestations, seizures and cognitive decline starting in her mid 20 s. Similarly affected relatives were observed in seven generations. Several of the affected individuals had post-mortem neuropathological brain study confirmatory for NCL disease. We conducted whole exome sequencing of three affected family members and identified a pLeu116del mutation in the gene DNAJC5, which segregated with the disease phenotype. An additional eight unrelated affected individuals with documented autosomal dominant or sporadic inheritance were studied. All had diagnostic confirmation with neuropathological studies of brain tissue. Among them we identified an additional individual with a p.Leu115Arg mutation in DNAJC5. In addition, a pAsn477Ser change in the neighboring gene PRPF6, a gene previously found to be associated with retinitis pigmentosa, segregated with the ADKD phenotype. Interestingly, two individuals of the Parry family did report visual impairment. Conclusions: Our study confirmed the recently reported association of DNAJC5 mutations with ADKD in two out of nine well-defined families. Sequence changes in PRPF6 have not been identified in other unrelated cases. The association of vision impairment with the expected PRPF6 dysfunction remains possible but would need further clinical studies in order to confirm the co-segregation of the visual impairment with this sequence change.

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