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Published on: August 20, 2019
Developmental dysplasia of the hip caused by homozygous TRIM33 pathogenic variant affecting downstream BMP pathway
Maya Gombosh1, Regina Proskorovski-Ohayon1, Yuval Yogev1
1Morris Kahn Laboratory of Human Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Insights
Developmental dysplasia of the hip (DDH) can be caused by genetic variants in the TRIM33 gene, impacting bone formation pathways. This finding sheds light on the molecular basis of DDH, a common newborn musculoskeletal condition.
Area of Science:
- Genetics
- Molecular Biology
- Orthopedics
Background:
- Developmental dysplasia of the hip (DDH) is the most common congenital musculoskeletal disorder in newborns.
- Familial patterns of DDH are recognized, but its molecular genetic causes remain largely unknown.
Purpose of the Study:
- To investigate the genetic basis of DDH in a consanguineous family with apparent autosomal recessive inheritance.
- To identify specific genes and pathways involved in DDH pathogenesis.
Main Methods:
- Linkage analysis and whole exome sequencing were performed on affected individuals.
- Real-time PCR studies on skin fibroblasts were used to analyze gene expression downstream of TRIM33 in the BMP pathway.
Main Results:
- A homozygous variant (c.1648_1650dup) in the TRIM33 gene was identified as the cause of DDH in the studied kindred.
- TRIM33 variants significantly altered the expression of downstream genes in the BMP pathway, including reduced DLX5 and increased BGLAP and ALPL expression in affected individuals.
Conclusions:
- Biallelic variants in TRIM33 can cause DDH by affecting the bone morphogenetic protein (BMP) pathway.
- This study identifies TRIM33 as a novel gene associated with DDH, providing insights into its molecular mechanisms.
Background:
Developmental dysplasia of the hip (DDH), formerly termed congenital dislocation of the hip, is the most common congenital disease of the musculoskeletal system in newborns. While familial predilection to DDH has been well documented, the molecular genetics/pathways of this common disorder are poorly understood.
Methods:
Linkage analysis and whole exome sequencing; real-time PCR studies of skin fibroblasts.
Results:
Consanguineous Bedouin kindred presented with DDH with apparent autosomal recessive heredity. Linkage analysis and whole exome sequencing delineated a single 3.2 Mbp disease-associated chromosome 1 locus (maximal multipoint Logarithm of the Odds score 2.3), containing a single homozygous variant with a relevant expression pattern: addition of threonine in TRIM33 (NM_015906.4); c.1648_1650dup. TRIM33 encodes a protein that acts both in the TGF-β and the BMP pathways; however, it has been mostly studied regarding its function in the TGF-β pathway. Since BMPs are known to act in bone formation, we focused on the BMP pathway, in which TRIM33 functions as a transcription factor, both an activator and repressor. Skin fibroblasts of two affected girls and a heterozygous TRIM33 variant carrier were assayed through reverse-transcription PCR for expression of genes known to be downstream of TRIM33 in the BMP pathway: fibroblasts of affected individuals showed significantly reduced expression of DLX5, significantly increased expression of BGLAP, increased expression of ALPL and no change in expression of RUNX2 or of TRIM33 itself.
Conclusions:
DDH can be caused by a biallelic variant in TRIM33, affecting the BMP pathway.
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