Autosomal recessive POLR1D mutation with decrease of TCOF1 mRNA is responsible for Treacher Collins syndrome
Elise Schaefer1, Corinne Collet2, David Genevieve3
11] Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, CHU de Hautepierre, Strasbourg, France [2] Laboratoire de Génétique Médicale, INSERM U1112, Faculté de Médecine, Université de Strasbourg, Strasbourg, France.
Purpose:
Treacher Collins syndrome is a mandibulofacial dysostosis caused by mutations in genes involved in ribosome biogenesis and synthesis. TCOF1 mutations are observed in ~80% of the patients and are inherited in an autosomal dominant manner. Recently, two other genes have been reported in <2% of patients--POLR1D in patients with autosomal dominant inheritance, and POLR1C in patients with autosomal recessive inheritance.
Methods:
We performed direct sequencing of TCOF1, POLR1C, and POLR1D in two unrelated consanguineous families.
Results:
The four affected children shared the same homozygous mutation in POLR1D (c.163C>G, p.Leu55Val). This mutation is localized in a region encoding the dimerization domain of the RNA polymerase. It is supposed that this mutation impairs RNA polymerase, resulting in a lower amount of mature dimeric ribosomes. A functional analysis of the transcripts of TCOF1 by real-time quantitative reverse transcription-polymerase chain reaction was performed in the first family, demonstrating a 50% reduction in the index case, compatible with this hypothesis.
Conclusion:
This is the first report of POLR1D mutation being responsible for an autosomal recessive inherited Treacher Collins syndrome. These results reinforce the concept of genetic heterogeneity of Treacher Collins syndrome and underline the importance of combining clinical expertise and familial molecular analyses for appropriate genetic counseling.
Insights
This study identifies a novel homozygous POLR1D mutation causing autosomal recessive Treacher Collins syndrome. This finding expands the genetic understanding of this rare mandibulofacial dysostosis.
Area of Science:
- Genetics
- Molecular Biology
- Developmental Biology
Background:
- Treacher Collins syndrome is a mandibulofacial dysostosis.
- Mutations in TCOF1 account for ~80% of cases, typically inherited in an autosomal dominant manner.
- POLR1D and POLR1C mutations have been reported in a small percentage of patients.
Purpose of the Study:
- To investigate the genetic basis of Treacher Collins syndrome in two consanguineous families.
- To identify novel gene mutations responsible for the disorder.
- To elucidate the inheritance pattern and molecular mechanisms.
Main Methods:
- Direct sequencing of TCOF1, POLR1C, and POLR1D genes.
- Analysis of genetic variants in affected individuals from two families.
- Functional analysis of TCOF1 transcripts using real-time quantitative reverse transcription-polymerase chain reaction.
Main Results:
- A shared homozygous mutation (c.163C>G, p.Leu55Val) in POLR1D was identified in four affected children.
- This POLR1D mutation affects the RNA polymerase dimerization domain, potentially impairing ribosome biogenesis.
- Functional analysis showed a 50% reduction in TCOF1 transcripts in the index case, supporting the proposed mechanism.
Conclusions:
- This study reports the first instance of a POLR1D mutation causing autosomal recessive Treacher Collins syndrome.
- The findings highlight the genetic heterogeneity of Treacher Collins syndrome.
- Emphasizes the importance of integrated clinical and molecular analysis for accurate genetic diagnosis and counseling.
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