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Compound heterozygosity for a frameshift mutation and an upstream deletion that reduces expression ofSERPINH1in siblings with a moderate form of osteogenesis imperfecta
- Source :
- American Journal of Medical Genetics Part A.
- Publication Year :
- 2019
- Publisher :
- Wiley, 2019.
-
Abstract
- SERPINH1 encodes the collagen chaperone HSP47 that binds to arginine-rich sequences in the type I procollagen trimers and provides the final steps in the folding and stabilization of the triple helical domain. Loss of both alleles in mice results in very early embryonic lethality. SERPINH1 mutations have been associated with one of the rarest forms of recessively inherited osteogenesis imperfecta (OI) with a moderate to severe phenotype. We identified a family with non-consanguineous unaffected parents who had two children with moderate short stature, low bone density, and fractures. Both children were compound heterozygotes for two mutations: a frameshift in the last exon that deleted the RER retention signal, and a 5,274 bp deletion 2.37 kb upstream from the transcription start site. The maternally-inherited frameshift allele was expressed at normal levels, but the protein was unstable. The mRNA encoded by the second allele represented about 50% of that from the frameshift-containing allele. The upstream deletion was inherited from the father, and the mRNA encoded by that allele in his cultured dermal fibroblasts was also expressed at a low level, which confirmed that this domain had a regulatory function for SERPINH1. Regulatory mutations are uncommon causes of human genetic disorders, and the ability to measure expression levels in appropriate cells is key to their identification.
- Subjects :
- Male
0301 basic medicine
Heterozygote
DNA Mutational Analysis
Primary Cell Culture
Gene Expression
030105 genetics & heredity
Biology
Compound heterozygosity
Severity of Illness Index
Short stature
Collagen Type I
Frameshift mutation
Fractures, Bone
03 medical and health sciences
Exon
Genetics
medicine
Humans
Allele
Child
Frameshift Mutation
HSP47 Heat-Shock Proteins
Alleles
Genetics (clinical)
Sequence Deletion
Siblings
Exons
Fibroblasts
Osteogenesis Imperfecta
medicine.disease
Phenotype
Pedigree
Collagen Type I, alpha 1 Chain
030104 developmental biology
Osteogenesis imperfecta
Chaperone (protein)
biology.protein
Female
medicine.symptom
Subjects
Details
- ISSN :
- 15524833 and 15524825
- Database :
- OpenAIRE
- Journal :
- American Journal of Medical Genetics Part A
- Accession number :
- edsair.doi.dedup.....04c25ff40e8d2559b000efdf28fddad4