ArticleAmerican journal of human genetics2014
Mutations affecting the BHLHA9 DNA-binding domain cause MSSD, mesoaxial synostotic syndactyly with phalangeal reduction, Malik-Percin type.
Article in American journal of human genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 32 citations in OpenAlex.
- Article
- Case Report: Compound heterozygous variants inFrontiers in pediatrics · 2025Article
- Sequence Variants in theMolecular syndromology · 2023Article
- Refining the Clinical Spectrum of the 17p13.3 Microduplication Syndrome: Case-Report of a Familial Small Microduplication.Biomedicines · 2022Article
- Developmental genomics of limb malformations: Allelic series in association with gene dosage effects contribute to the clinical variability.HGG advances · 2022Article
- SHFLD3 phenotypes caused by 17p13.3 triplication/ duplication encompassing Fingerin (BHLHA9) invariably.Orphanet journal of rare diseases · 2022Article
- Need for revision of the ACMG/AMP guidelines for interpretation of X-linked variants.Intractable & rare diseases research · 2022Article
- Homodimeric and Heterodimeric Interactions among Vertebrate Basic Helix-Loop-Helix Transcription Factors.International journal of molecular sciences · 2021Review
- A Novel Missense Variant ofBioMed research international · 2020Article
- Split hand/foot malformation with long bone deficiency associated with BHLHA9 gene duplication: a case report and review of literature.BMC medical genetics · 2019Review
- 17p13.3 genomic rearrangement in a Chinese family with split-hand/foot malformation with long bone deficiency: report of a complicated duplication with marked variation in phenotype.Orphanet journal of rare diseases · 2018Article
- Noncoding copy-number variations are associated with congenital limb malformation.Genetics in medicine : official journal of the American College of Medical Genetics · 2018Article
- Mesoaxial synostotic syndactyly with phalangeal reduction (MSSD): syndactyly type IX.Skeletal radiology · 2018Article
- Bhlha9 regulates apical ectodermal ridge formation during limb development.Journal of bone and mineral metabolism · 2018Article
- Copy-number variants and candidate gene mutations in isolated split hand/foot malformation.Journal of human genetics · 2017Article
- A New Split Hand/Foot Malformation with Long Bone Deficiency Familial Case.Journal of pediatric genetics · 2017Article
- Limb development: a paradigm of gene regulation.Nature reviews. Genetics · 2017Review
- A novel homozygous missense mutation inHuman genome variation · 2017Article
- Monogenic Autoinflammatory Diseases with Mendelian Inheritance: Genes, Mutations, and Genotype/Phenotype Correlations.Frontiers in immunology · 2017Review
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Authors and funding
12 authors at 6 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mesoaxial synostotic syndactyly, Malik-Percin type (MSSD) (syndactyly type IX) is a rare autosomal-recessive nonsyndromic digit anomaly with only two affected families reported so far. We previously showed that the trait is genetically distinct from other syndactyly types, and through autozygosity mapping we had identified a locus on chromosome 17p13.3 for this unique limb malformation. Here, we extend the number of independent pedigrees from various geographic regions segregating MSSD to a total of six. We demonstrate that three neighboring missense mutations affecting the highly conserved DNA-binding region of the basic helix-loop-helix A9 transcription factor (BHLHA9) are associated with this phenotype. Recombinant BHLHA9 generated by transient gene expression is shown to be located in the cytoplasm and the cell nucleus. Transcription factors 3, 4, and 12, members of the E protein (class I) family of helix-loop-helix transcription factors, are highlighted in yeast two-hybrid analysis as potential dimerization partners for BHLHA9. In the presence of BHLHA9, the potential of these three proteins to activate expression of an E-box-regulated target gene is reduced considerably. BHLHA9 harboring one of the three substitutions detected in MSSD-affected individuals eliminates entirely the transcription activation by these class I bHLH proteins. We conclude that by dimerizing with other bHLH protein monomers, BHLHA9 could fine tune the expression of regulatory factors governing determination of central limb mesenchyme cells, a function made impossible by altering critical amino acids in the DNA binding domain. These findings identify BHLHA9 as an essential player in the regulatory network governing limb morphogenesis in humans.
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