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Mutations in C16orf57 and normal-length telomeres unify a subset of patients with dyskeratosis congenita, poikiloderma with neutropenia and Rothmund-Thomson syndrome.

Walne AJ, Vulliamy T, Beswick R, Kirwan M, Dokal I - Hum. Mol. Genet. (2010)

Bottom Line: Analysis of the C16orf57 gene in our uncharacterized DC patients revealed homozygous mutations in 6 of 132 families.Given the role of the previous DC genes in telomere maintenance, telomere length was analysed in these patients and found to be comparable to age-matched controls.These findings suggest that mutations in C16orf57 unify a distinct set of families which clinically can be categorized as DC, PN or RTS.

View Article: PubMed Central - PubMed

Affiliation: Centre for Paediatrics, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Barts and The London Children’s Hospital, 4 Newark Street, London, UK. a.walne@qmul.ac.uk

ABSTRACT
Dyskeratosis congenita (DC) is an inherited poikiloderma which in addition to the skin abnormalities is typically associated with nail dystrophy, leucoplakia, bone marrow failure, cancer predisposition and other features. Approximately 50% of DC patients remain genetically uncharacterized. All the DC genes identified to date are important in telomere maintenance. To determine the genetic basis of the remaining cases of DC, we undertook linkage analysis in 20 families and identified a common candidate gene region on chromosome 16 in a subset of these. This region included the C16orf57 gene recently identified to be mutated in poikiloderma with neutropenia (PN), an inherited poikiloderma displaying significant clinical overlap with DC. Analysis of the C16orf57 gene in our uncharacterized DC patients revealed homozygous mutations in 6 of 132 families. In addition, three of six families previously classified as Rothmund-Thomson syndrome (RTS-a poikiloderma that is sometimes confused with PN) were also found to have homozygous C16orf57 mutations. Given the role of the previous DC genes in telomere maintenance, telomere length was analysed in these patients and found to be comparable to age-matched controls. These findings suggest that mutations in C16orf57 unify a distinct set of families which clinically can be categorized as DC, PN or RTS. This study also highlights the multi-system nature (wider than just poikiloderma and neutropenia) of the clinical features of affected individuals (and therefore house-keeping function of C16orf57), a possible role for C16orf57 in apoptosis, as well as a distinct difference from previously characterized DC patients because telomere length was normal.

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Pedigrees of families with mutations in C16orf57. Sequence panel on the left shows the normal trace while the right shows the observed mutation. The arrow highlights the point of mutation. c., coding nucleotide number; nd, sample unavailable for analysis; open shape, unaffected individual; filled shape, affected individual.
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DDQ371F2: Pedigrees of families with mutations in C16orf57. Sequence panel on the left shows the normal trace while the right shows the observed mutation. The arrow highlights the point of mutation. c., coding nucleotide number; nd, sample unavailable for analysis; open shape, unaffected individual; filled shape, affected individual.

Mentions: Using the UCSC genome bioinformatics site (http://genome.ucsc.edu), 22 genes were found to be in this region, none of which were obvious candidates. Out of these 22 genes, snoRNA46, snoRNA50, GINS3 and CSNK2A2 were sequenced, but no mutation was identified. A recent paper by Volpi et al. (17) described a homozygous splicing mutation in the orphan gene C16orf57, in a large kindred with PN. Owing to the clinical overlap between the published family and our DCR families, we sequenced this gene in the index case from DCR070, DCR107, DCR224 and DCR279 as well as the sporadic individuals from DCR106, DCR311 and DCR324 which also overlapped this interval. Homozygous mutations were identified in all patients except DCR311 and DCR324 (Table 1). Where a mutation was observed, the rest of the family was sequenced for that exon to confirm the presence of the mutation in the index case and to determine segregation (Fig. 2).Table 1.


Mutations in C16orf57 and normal-length telomeres unify a subset of patients with dyskeratosis congenita, poikiloderma with neutropenia and Rothmund-Thomson syndrome.

Walne AJ, Vulliamy T, Beswick R, Kirwan M, Dokal I - Hum. Mol. Genet. (2010)

Pedigrees of families with mutations in C16orf57. Sequence panel on the left shows the normal trace while the right shows the observed mutation. The arrow highlights the point of mutation. c., coding nucleotide number; nd, sample unavailable for analysis; open shape, unaffected individual; filled shape, affected individual.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2957322&req=5

DDQ371F2: Pedigrees of families with mutations in C16orf57. Sequence panel on the left shows the normal trace while the right shows the observed mutation. The arrow highlights the point of mutation. c., coding nucleotide number; nd, sample unavailable for analysis; open shape, unaffected individual; filled shape, affected individual.
Mentions: Using the UCSC genome bioinformatics site (http://genome.ucsc.edu), 22 genes were found to be in this region, none of which were obvious candidates. Out of these 22 genes, snoRNA46, snoRNA50, GINS3 and CSNK2A2 were sequenced, but no mutation was identified. A recent paper by Volpi et al. (17) described a homozygous splicing mutation in the orphan gene C16orf57, in a large kindred with PN. Owing to the clinical overlap between the published family and our DCR families, we sequenced this gene in the index case from DCR070, DCR107, DCR224 and DCR279 as well as the sporadic individuals from DCR106, DCR311 and DCR324 which also overlapped this interval. Homozygous mutations were identified in all patients except DCR311 and DCR324 (Table 1). Where a mutation was observed, the rest of the family was sequenced for that exon to confirm the presence of the mutation in the index case and to determine segregation (Fig. 2).Table 1.

Bottom Line: Analysis of the C16orf57 gene in our uncharacterized DC patients revealed homozygous mutations in 6 of 132 families.Given the role of the previous DC genes in telomere maintenance, telomere length was analysed in these patients and found to be comparable to age-matched controls.These findings suggest that mutations in C16orf57 unify a distinct set of families which clinically can be categorized as DC, PN or RTS.

View Article: PubMed Central - PubMed

Affiliation: Centre for Paediatrics, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Barts and The London Children’s Hospital, 4 Newark Street, London, UK. a.walne@qmul.ac.uk

ABSTRACT
Dyskeratosis congenita (DC) is an inherited poikiloderma which in addition to the skin abnormalities is typically associated with nail dystrophy, leucoplakia, bone marrow failure, cancer predisposition and other features. Approximately 50% of DC patients remain genetically uncharacterized. All the DC genes identified to date are important in telomere maintenance. To determine the genetic basis of the remaining cases of DC, we undertook linkage analysis in 20 families and identified a common candidate gene region on chromosome 16 in a subset of these. This region included the C16orf57 gene recently identified to be mutated in poikiloderma with neutropenia (PN), an inherited poikiloderma displaying significant clinical overlap with DC. Analysis of the C16orf57 gene in our uncharacterized DC patients revealed homozygous mutations in 6 of 132 families. In addition, three of six families previously classified as Rothmund-Thomson syndrome (RTS-a poikiloderma that is sometimes confused with PN) were also found to have homozygous C16orf57 mutations. Given the role of the previous DC genes in telomere maintenance, telomere length was analysed in these patients and found to be comparable to age-matched controls. These findings suggest that mutations in C16orf57 unify a distinct set of families which clinically can be categorized as DC, PN or RTS. This study also highlights the multi-system nature (wider than just poikiloderma and neutropenia) of the clinical features of affected individuals (and therefore house-keeping function of C16orf57), a possible role for C16orf57 in apoptosis, as well as a distinct difference from previously characterized DC patients because telomere length was normal.

Show MeSH
Related in: MedlinePlus