Bone Marrow Failure Syndrome 1

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Retrieved

2019-09-22

Source

Omim

Trials

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Genes

SRP72, CSF2, DNAJC21, ERCC6L2

Drugs

Allogeneic multi-virus specific T lymphocytes targeting BK virus, cytomegalovirus, human herpesvirus-6, Epstein Barr virus and adenovirus, haematopoietic stem cells and blood progenitors umbilical cord-derived expanded with (1R, 4R)-N1-(2-benzyl-7-(2-methyl-2H-tetrazol-5-yl)-9H-pyrimido[4,5-b]indol-4-yl)cyclohexane-1,4-diamine dihydrobromide dihydrate

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A number sign (#) is used with this entry because autosomal dominant bone marrow failure syndrome-1 (BMFS1) is caused by heterozygous mutation in the SRP72 gene (602122) on chromosome 4q12.

Genetic Heterogeneity of Bone Marrow Failure Syndrome

See also BMFS2 (615715), caused by mutation in the ERCC6L2 gene (615667) on chromosome 9q22; BMSF3 (617052), caused by mutation in the DNAJC21 gene (617048) on chromosome 5p13; BMFS4 (618116), caused by mutation in the MYSM1 gene (612176) on chromosome 1p32; and BMFS5 (618165), caused by mutation in the TP53 gene (191170) on chromosome 17p13.

Clinical Features

Kirwan et al. (2012) reported a family in which 3 sibs, aged 11 to 14 years, had early-onset aplastic anemia or pancytopenia and their mother had myelodysplasia. All also had congenital nerve deafness. None were treated for the hematologic abnormalities. In a second family, both a mother and daughter had adult-onset myelodysplasia. Neither had deafness, but the daughter had possible labyrinthitis. Neither received treatment.

Inheritance

The transmission pattern of bone marrow failure in the families reported by Kirwan et al. (2012) was consistent with autosomal dominant inheritance.

Molecular Genetics

By whole-exome sequencing, Kirwan et al. (2012) identified a truncating mutation in the SRP72 gene (602122.0001) in 4 affected members of a family with autosomal dominant aplastic anemia/myelodysplasia and congenital deafness. Screening of this gene in 96 additional individuals with bone marrow failure identified 1 woman with myelodysplasia who had a heterozygous missense mutation (R207H; 602122.0002); her mother with myelodysplasia also carried the mutation. In vitro functional expression studies showed that both mutant proteins had reduced colocalization with ER markers compared to wildtype. The truncating mutation showed a marked reduction in coprecipitation with 7SL RNA (see, e.g., RN7SL1, 612177), whereas the R207H mutant protein had increased interaction with 7SL RNA. These defects were predicted to interfere with normal functioning of the signal recognition particle, with a failure to arrest cytoplasmic translation or properly translocate peptides within the cell. However, it was unclear how a defect in protein translocation would result in the phenotype.