t(6;20)(q13;q12) LMBRD1/CHD6

2014-04-01   Nathalie Douet-Guilbert , Etienne De Braekeleer , Corinne Tous , Nadia Guéganic , Frédéric Morel , Marc De Braekeleer 

1.Cytogenetics Laboratory, Faculty of Medicine, University of Brest, France

Clinics and Pathology

Disease

Myelodysplastic syndrome/myeloproliferative disorder (MDS/MPD) in transformation (Acute myelocytic leukemia - AML)

Epidemiology

No cases registered in the Mitelman database.

Clinics

A 78-year-old woman seen because of worsening of cytopenias two years following diagnosis of MDS/MPD. No further investigations.

Evolution

Patient deceased soon after diagnosis of AML.

Cytogenetics

Note

The t(6;20)(q13;q12) involves two genes, the LMBRD1 and CHD6 genes, that have never been shown to form a fusion gene.
Atlas Image
RHG banding showing chromosomes 6 and 20 and the derivatives der(6) and der(20).

Cytogenetics morphological

t(6;20)(q13;q12) is identified by banding cytogenetics.

Cytogenetics molecular

To determine the position of the breakpoints on chromosomes 6 and 20, BACs located in the bands of interest were used as probes in FISH experiments. Analysis with RP11-359N1 showed that one signal hybridized to the normal chromosome 6, and the other split and hybridized to both der(6) and der(20). Analysis with RP11-257H6 showed that one signal hybridized to the normal chromosome 20, and the other split and hybridized to both der(6) and der(20). Co-hybridization with both BAC clones showed two fusion signals. RP11-359N1 contains the LMBRD1 gene and RP11-257H6 the CHD6 gene.
Atlas Image
FISH with BACs RP11-359N1 (spectrum green, located in 6q13 and containing LMBRD1) and RP11-257H6 (spectrum orange, located in 20q12 and containing CHD6) showing co-hybridization.

Genes Involved and Proteins

Gene name
LMBRD1 (LMBR1 domain containing 1)
Location
6q13
Note
Mutations in the LMBRD1 gene is responsible for methylmalonic aciduria and homocystinuria type cblF (autosomal recessive disorder). It is a disorder of cobalamin metabolism characterized by decreased levels of the coenzymes adenosylcobalamin and methylcobalamin due to accumulation of free cobalamin in lysosomes, thus preventing its conversion to cofactors.
Clinical features include poor feeding, failure to thrive, developmental delay, stomatitis, glossitis, seizures, macrocytic anemia, neutropenia, thrombocytopenia and methylmalonic aciduria responsive to vitamin B12.
Dna rna description
The LMBRD1 gene contains 15 exons, spanning 115 kb. Three transcripts (splice variants) are known, two being protein coding.
Protein description
The protein has 540 amino acids (61.4 kDa) and localizes to the lysosome membrane. It contains nine transmembrane helices and six putative glycosylation sites with an N terminus in the lysosomal interior and a cytoplasmatic C terminus. It is a probable lysosomal cobalamin transporter, being required to export cobalamin from lysosomes, which in turn allows its conversion to cofactors. It also appears to play a key role in mediating and regulating the endocytosis of the insulin receptor. Isoform 3 coding the nuclear export signal interacting protein (NESI) may play a role in the assembly of hepatitis delta virus.
Gene name
CHD6 (chromodomain helicase DNA binding protein 6)
Location
20q12
Note
The CHD6 gene, located 403 kb centromeric to STS marker D20S108 is constantly deleted in MDS and MPD associated with del(20q) or ider(20q).
Dna rna description
The CHD6 gene contains 37 exons of which 36 are coding, spanning 216 kb. Nine transcripts are known.
Protein description
The gene encodes a member of the SNF2/RAD54 helicase protein family. The protein has 2715 amino acids (305 kDa) and localizes to the nucleus. It contains two chromodomains, a helicase domain, and an ATPase domain. The protein is thought to be a core member of one or more of chromatin remodelling complexes. It may function as a transcriptional repressor. It is involved in the cellular repression of influenza virus replication and in transcriptional repression of papillomavirus.

Bibliography

Pubmed IDLast YearTitleAuthors
218996942011CHD6 chromatin remodeler is a negative modulator of influenza virus replication that relocates to inactive chromatin upon infection.Alfonso R et al
190360152008Fluorescence in situ hybridization characterization of ider(20q) in myelodysplastic syndrome.Douet-Guilbert N et al
206311452010Interaction of the papillomavirus E8--E2C protein with the cellular CHD6 protein contributes to transcriptional repression.Fertey J et al
201747752010Insights into lysosomal cobalamin trafficking: lessons learned from cblF disease.Gailus S et al
201274172010A novel mutation in LMBRD1 causes the cblF defect of vitamin B(12) metabolism in a Turkish patient.Gailus S et al
231753582013Nuclear export signal-interacting protein forms complexes with lamin A/C-Nups to mediate the CRM1-independent nuclear export of large hepatitis delta antigen.Huang C et al
170279772006CHD6 is a DNA-dependent ATPase and localizes at nuclear sites of mRNA synthesis.Lutz T et al
173506552007The Chd family of chromatin remodelers.Marfella CG et al
213037342011Novel splice site mutations and a large deletion in three patients with the cblF inborn error of vitamin B12 metabolism.Miousse IR et al
204461152011LMBRD1: the gene for the cblF defect of vitamin B₁₂ metabolism.Rutsch F et al
118895612002CHD5 defines a new subfamily of chromodomain-SWI2/SNF2-like helicases.Schuster EF et al
240786302013LMBD1 protein serves as a specific adaptor for insulin receptor internalization.Tseng LT et al
159565562005Novel nuclear export signal-interacting protein, NESI, critical for the assembly of hepatitis delta virus.Wang YH et al

Citation

Nathalie Douet-Guilbert ; Etienne De Braekeleer ; Corinne Tous ; Nadia Guéganic ; Frédéric Morel ; Marc De Braekeleer

t(6;20)(q13;q12) LMBRD1/CHD6

Atlas Genet Cytogenet Oncol Haematol. 2014-04-01

Online version: http://atlasgeneticsoncology.org/haematological/1678/t(6;20)(q13;q12)

External Links