Bhlha9, also known as Fingerin, is a gene whose encoded protein is predicted to function as a transcription factor. It is involved in limb development, particularly in the regulation of apical ectodermal ridge (AER) formation, a crucial process for proper limb and finger development [2].

Gene knockout studies in mice have shown that Bhlha9-knockout mice exhibit syndactyly and poliosis in the limb [2]. Additionally, genes related to AER formation, such as Trp63, display an aberrant expression pattern in the limb bud of these knockout mice, and in vitro analysis indicates that TP63 (Trp63) is regulated by Bhlha9 [2]. In human studies, duplications of the BHLHA9 gene, often in the 17p13.3 locus, are associated with split-hand/foot malformation with long-bone deficiency (SHFLD), a rare condition where SHFM is combined with long-bone malformation, usually of the tibia [1,3,4,5,6]. In a consanguineous Lebanese family, a homozygous duplication of BHLHA9 was found in members with limb abnormalities including tibial hemimelia, and this duplication presented challenges for genetic counseling due to incomplete penetrance and variable expressivity of the disease [1].

In conclusion, Bhlha9 plays an essential role in limb development by regulating AER-formation-related genes. Studies using gene knockout mouse models have provided insights into its function in limb development, and human genetic studies have linked Bhlha9 duplications to the occurrence of SHFLD. These findings contribute to our understanding of the genetic basis of limb-related congenital disorders.

References:

1. Chouery, Eliane, Tahan, Elio, Karam, Rim, Mehawej, Cybel, Megarbane, Andre. 2022. BHLHA9 homozygous duplication in a consanguineous family: A challenge for genetic counseling. In American journal of medical genetics. Part A, 191, 923-929. doi:10.1002/ajmg.a.63094. https://pubmed.ncbi.nlm.nih.gov/36565049/

2. Kataoka, Kensuke, Matsushima, Takahide, Ito, Yoshiaki, Yokoyama, Shigetoshi, Asahara, Hiroshi. 2017. Bhlha9 regulates apical ectodermal ridge formation during limb development. In Journal of bone and mineral metabolism, 36, 64-72. doi:10.1007/s00774-017-0820-0. https://pubmed.ncbi.nlm.nih.gov/28324176/

3. Paththinige, Chamara Sampath, Sirisena, Nirmala Dushyanthi, Escande, Fabienne, Petit, Florence, Dissanayake, Vajira Harshadeva Weerabaddana. 2019. Split hand/foot malformation with long bone deficiency associated with BHLHA9 gene duplication: a case report and review of literature. In BMC medical genetics, 20, 108. doi:10.1186/s12881-019-0839-2. https://pubmed.ncbi.nlm.nih.gov/31200655/

4. Curry, Cynthia J, Rosenfeld, Jill A, Grant, Erica, Shaffer, Lisa G, Dobyns, William B. 2013. The duplication 17p13.3 phenotype: analysis of 21 families delineates developmental, behavioral and brain abnormalities, and rare variant phenotypes. In American journal of medical genetics. Part A, 161A, 1833-52. doi:10.1002/ajmg.a.35996. https://pubmed.ncbi.nlm.nih.gov/23813913/

5. Bukowska-Olech, Ewelina, Sowińska-Seidler, Anna, Wierzba, Jolanta, Jamsheer, Aleksander. 2022. SHFLD3 phenotypes caused by 17p13.3 triplication/ duplication encompassing Fingerin (BHLHA9) invariably. In Orphanet journal of rare diseases, 17, 325. doi:10.1186/s13023-022-02480-w. https://pubmed.ncbi.nlm.nih.gov/36028842/

6. Petit, F, Jourdain, A-S, Andrieux, J, Manouvrier-Hanu, S, Escande, F. 2013. Split hand/foot malformation with long-bone deficiency and BHLHA9 duplication: report of 13 new families. In Clinical genetics, 85, 464-9. doi:10.1111/cge.12219. https://pubmed.ncbi.nlm.nih.gov/23790188/