Format

Send to

Choose Destination
Am J Hum Genet. 2016 Feb 4;98(2):339-46. doi: 10.1016/j.ajhg.2015.12.007. Epub 2016 Jan 21.

Mitotic Intragenic Recombination: A Mechanism of Survival for Several Congenital Disorders of Glycosylation.

Author information

1
NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA; National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA. Electronic address: megan.kane@nih.gov.
2
NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA; National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
3
NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA.
4
NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA; Department of Neurology, Children's National Medical Center, Washington, DC 20010, USA.
5
Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
6
NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA; National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA. Electronic address: gahlw@helix.nih.gov.
7
Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.

Abstract

Congenital disorders of glycosylation (CDGs) are disorders of abnormal protein glycosylation that affect multiple organ systems. Because most CDGs have been described in only a few individuals, our understanding of the associated phenotypes and the mechanisms of individual survival are limited. In the process of studying two siblings, aged 6 and 11 years, with MOGS-CDG and biallelic MOGS (mannosyl-oligosaccharide glucosidase) mutations (GenBank: NM_006302.2; c.[65C>A; 329G>A] p.[Ala22Glu; Arg110His]; c.[370C>T] p.[Gln124(∗)]), we noted that their survival was much longer than the previous report of MOGS-CDG, in a child who died at 74 days of age. Upon mutation analysis, we detected multiple MOGS genotypes including wild-type alleles in their cultured fibroblast and peripheral blood DNA. Further analysis of DNA from cultured fibroblasts of six individuals with compound heterozygous mutations of PMM2 (PMM2-CDG), MPI (MPI-CDG), ALG3 (ALG3-CDG), ALG12 (ALG12-CDG), DPAGT1 (DPAGT1-CDG), and ALG1 (ALG1-CDG) also identified multiple genotypes including wild-type alleles for each. Droplet digital PCR showed a ratio of nearly 1:1 wild-type to mutant alleles for most, but not all, mutations. This suggests that mitotic recombination contributes to the survival and the variable expressivity of individuals with compound heterozygous CDGs. This also provides an explanation for prior observations of a reduced frequency of homozygous mutations and might contribute to increased levels of residual enzyme activity in cultured fibroblasts of individuals with MPI- and PMM2-CDGs.

PMID:
26805780
PMCID:
PMC4746335
DOI:
10.1016/j.ajhg.2015.12.007
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center