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Grebe dysplasia and the spectrum of CDMP1 mutations
Christiane Stelzer1, Andreas Winterpacht, Jürgen Spranger
1Children's Hospital, University of Mainz, Langenbeckstr. 1, D-55101 Mainz, Germany.
Insights
Grebe dysplasia is caused by a CDMP1 gene mutation. Homozygous mutations lead to severe skeletal dysplasia, while heterozygous mutations cause milder brachydactyly type C.
Area of Science:
- Genetics
- Skeletal Dysplasias
- Molecular Biology
Background:
- Grebe dysplasia is a rare skeletal disorder characterized by severe limb shortening.
- Autosomal recessive inheritance is typically associated with Grebe dysplasia.
- The genetic basis of Grebe dysplasia has been linked to mutations in the cartilage-derived morphogenetic protein 1 (CDMP1) gene.
Observation:
- A 4-year-old boy presented with typical Grebe dysplasia phenotype.
- His parents were consanguineous, with the mother exhibiting brachydactyly type C (BdC).
- Genetic analysis revealed a heterozygous G insertion at nucleotide 206 in the CDMP1 gene in the mother and homozygous insertion in the affected child.
Findings:
- The identified CDMP1 mutation (insG206) causes a frameshift and premature termination, leading to functional haploinsufficiency.
- The phenotypic spectrum associated with this loss-of-function mutation ranges from normal or BdC in heterozygotes to Grebe-type chondrodysplasia in homozygotes.
- These findings suggest CDMP1 gradient effects during pattern formation are responsible for the observed phenotypes.
Implications:
- This study elucidates the genotype-phenotype correlation for CDMP1 mutations in skeletal dysplasias.
- Understanding CDMP1's role in skeletogenesis provides insights into limb development.
- The findings may inform genetic counseling and potential therapeutic strategies for related disorders.
Abstract:
We report on a 4-year-old boy with the typical phenotype of Grebe dysplasia born to consanguineous parents. The father seems to be unaffected; the mother presents with brachydactyly type C (BdC). PCR amplification and sequencing of the cartilage-derived morphogenetic protein 1 (CDMP1) gene of the parents led to the identification of a heterozygous insertion of a single G at nucleotide 206. The mutation that causes frameshift and premature termination is predicted to result in functional haploinsufficiency. The child is homozygous for the insertion (insG206). The phenotypic spectrum of this loss-of-function mutation ranges from normal or BdC in heterozygotes to Grebe-type chondrodysplasia in the homozygously affected and seems to be due to CDMP1 gradient effects during pattern formation. A dominant negative action on other bone morphogenetic proteins is unlikely to cause the severe disruption of skeletogenesis seen in this case of Grebe dysplasia.