ORPHA: 84; DO: 0111092;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16p13.3 | Fanconi anemia, complementation group P | 613951 | Autosomal recessive | 3 | SLX4 | 613278 |
A number sign (#) is used with this entry because Fanconi anemia of complementation group P (FANCP) is caused by homozygous or compound heterozygous mutation in the SLX4 gene (613278) on chromosome 16p13.
Fanconi anemia of complementation group P is an autosomal recessive disorder characterized by increased chromosomal instability and progressive bone marrow failure. Some patients have skeletal anomalies (summary by Kim et al., 2011).
For a general description and a discussion of genetic heterogeneity of Fanconi anemia (FA), see 227650.
Stoepker et al. (2011) reported a Dutch boy, born of consanguineous parents, with growth retardation, microcephaly, hypopigmentation, thumb abnormalities, and hearing loss who was diagnosed with pancytopenia at age 9 years. He also had some dysmorphic facial features, including small almond-shaped eyes, bulbous nasal tip, and micrognathia. He had a hypopigmented spot on his back and no renal anomalies. Lymphocyte cultures showed increased spontaneous and induced chromosomal breakage and aberrations, consistent with Fanconi anemia. In a second family, 3 German sibs had growth retardation and pancytopenia. One had a horseshoe kidney, and another had cafe-au-lait spots, but otherwise no physical abnormalities were reported. Lymphoblasts from these patients were sensitive to mitomycin C but not camptothecin.
Kim et al. (2011) reported 2 unrelated patients with FANCP. One patient was a 15-year-old girl from South India who presented at age 9 years with isolated thrombocytopenia. She had short stature and vitiligo. The other patient was an American man of European descent with bilateral absent thumbs and right radial aplasia, pelvic kidney, undescended left testicle, malformed auricle, and short stature, as well as low platelets and anemia. He developed squamous cell carcinoma of the tongue at age 21 years and died at age 22. Lymphoblasts and fibroblasts from both patients showed variable chromosomal instability upon exposure to mitomycin C and camptothecin.
In a Dutch boy, born of consanguineous parents, with FANCP, Stoepker et al. (2011) identified a homozygous truncating mutation in the SLX4 gene (613278.0001). The gene was chosen for study because of its known function as a scaffold protein in the DNA repair pathway. Stoepker et al. (2011) also identified compound heterozygous mutations in the SLX4 gene (613278.0002-613278.0003), which resulted in residual protein function, in 3 German sibs with a milder FANCP phenotype.
Kim et al. (2011) identified biallelic mutations in the SLX4 gene (613278.0004-613278.0006) in 2 unrelated patients with FANCP.
Crossan et al. (2011) found that Slx4-null mice recapitulated the features of Fanconi anemia in humans. Slx4-null mice were born at submendelian ratios and had greatly reduced fertility due to gonad dysfunction. Ovaries showed absence of oocytes, and testes showed progressive failure of spermatogenesis. Many mutant mice died soon after birth, and the survivors showed poor growth, with domed skulls and ocular anomalies. Mutant mice also showed blood cytopenia, indicating hematologic dysfunction. Cells derived from the mutant mice exhibited premature senescence, spontaneously accumulated damaged chromosomes, and were sensitive to DNA crosslinking agents, but not to UV radiation.
Crossan, G. P., van der Weyden, L., Rosado, I. V., Langevin, F., Gaillard, P.-H. L., McIntyre, R. E., Sanger Mouse Genetics Project, Gallagher, F., Kettunen, M. I., Lewis, D. Y., Brindle, K., Arends, M. J., Adams, D. J., Patel, K. J. Disruption of mouse Slx4, a regulator of structure-specific nucleases, phenocopies Fanconi anemia. Nature Genet. 43: 147-152, 2011. [PubMed: 21240276] [Full Text: https://doi.org/10.1038/ng.752]
Kim, Y., Lach, F. P., Desetty, R., Hanenberg, H., Auerbach, A. D., Smogorzewska, A. Mutations of the SLX4 gene in Fanconi anemia. Nature Genet. 43: 142-146, 2011. [PubMed: 21240275] [Full Text: https://doi.org/10.1038/ng.750]
Stoepker, C., Hain, K., Schuster, B., Hilhorst-Hofstee, Y., Rooimans, M. A., Steltenpool, J., Oostra, A. B., Eirich, K., Korthof, E. T., Nieuwint, A. W. M., Jaspers, N. G. J., Bettecken, T., Joenje, H., Schindler, D., Rouse, J., de Winter, J. P. SLX4, a coordinator of structure-specific endonucleases, is mutated in a new Fanconi anemia subtype. Nature Genet. 43: 138-141, 2011. [PubMed: 21240277] [Full Text: https://doi.org/10.1038/ng.751]