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Gene Review

SHFM1  -  split hand/foot malformation...

Homo sapiens

Synonyms: 26S proteasome complex subunit DSS1, DSS1, Deleted in split hand/split foot protein 1, ECD, SEM1, ...
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Disease relevance of SHFM1

  • Split hand-split foot malformation (SHFM) is a genetically heterogeneous limb developmental defect characterised by the absence of digital rays and syndactyly of the remaining digits [1].
  • Split hand/split foot malformation with hearing loss: first report of families linked to the SHFM1 locus in 7q21 [2].
  • Bilateral complete radioulnar synostosis associated with ectrodactyly and sensorineural hearing loss: a variant of SHFM1 [3].
  • Deletion or mutation of DSS1 or suppression of its expression by other mechanisms are therefore potential causative mechanisms for human breast and ovarian cancer [4].
  • Most notably, like BRCA2 depletion, DSS1 depletion also led to hypersensitivity to DNA damage [4].

Psychiatry related information on SHFM1


High impact information on SHFM1

  • The influence of the concentration of androgen present on the development of heterogeneous growth responsiveness to androgens was studied in an androgen-sensitive clone (SEM-1) of the Shionogi mammary carcinoma cell line incubated for up to 6 months in the presence of 0, 0.01, 0.3, or 100 nM dihydrotestosterone (DHT) [7].
  • Bronchodilatation was greater at 1600 h than at 0400 h in both the normal subjects (mean decrease in Ros 1-3 min after capsaicin at 1600 h 9% [SEM 1], at 0400 h -2% [1]; p less than 0.001) and the asthmatic group (1% [1], -7% [2]; p = 0.001) [8].
  • There appears to be a genotype-phenotype correlation, in that there is a specific pattern of missense mutations in EEC syndrome that are not generally found in SHFM or LMS [9].
  • Split-hand/split-foot malformation (SHFM), a limb malformation involving the central rays of the autopod and presenting with syndactyly, median clefts of the hands and feet, and aplasia and/or hypoplasia of the phalanges, metacarpals, and metatarsals, is phenotypically analogous to the naturally occurring murine Dactylaplasia mutant (Dac) [10].
  • We mapped data from a large Turkish family with isolated SHFM to chromosome 10q24 and have narrowed the SHFM3 region from 9 cM to an approximately 2-cM critical interval between genetic markers D10S1147 and D10S1240 [11].

Chemical compound and disease context of SHFM1


Biological context of SHFM1

  • Three disease loci have recently been mapped to chromosomes 7q21 (SHFM1), Xq26 (SHFM2), and 10q25 respectively (SHFM3) [1].
  • To investigate 10q25 as a possible split hand/split foot locus, microsatellite markers spanning 52 cM of 10q were utilized for linkage analysis of a large autosomal dominant SHSF pedigree in which the region encompassing SHFM1 previously was excluded as containing the causative mutation [15].
  • However, incomplete penetrance, variable expressivity, segregation distortion, and syndromic association with other anomalies have so far prevented the identification of the SHFM1 gene(s) in man [16].
  • Molecular genetic characterization of a Korean split hand/split foot malformation (SHFM) [17].
  • In the present study, marker loci were localized to the SHFD1 critical region through the analysis of somatic cell hybrids derived from individuals with SHSF and cytogenetic abnormalities involving the 7q21-q22 region [18].

Anatomical context of SHFM1

  • Here we show that the targeted double inactivation of Dlx5 and Dlx6 in the mouse causes in homozygous mutant animals bilateral ectrodactyly with a severe defect of the central ray of the hindlimbs, a malformation typical of SHFM1 [16].
  • SHFM is clinically heterogeneous, presenting both in an isolated form and in combination with additional abnormalities affecting the tibia and/or other organ systems, including the genitourinary, craniofacial, and ectodermal structures [11].
  • Importantly, we found that RNAi knockdown of DSS1 in human cell lines led to dramatic loss of BRCA2 protein, mainly due to its increased degradation [4].
  • Although 64 (SEM 4)% of the local inflammatory cells expressed Ia antigen, only 4 (SEM 1)% of them displayed the T cell activation antigen Tac [19].
  • Discrepancies in upper and lower limb patterning in split hand foot malformation.Split hand foot malformation (SHFM) is genetically heterogeneous with five loci mapped to date [20].

Associations of SHFM1 with chemical compounds

  • Here we report that although Calindol has little or no agonist activity in the absence of extracellular Ca(2+) for the ECD-containing wild type or carboxyl-terminal deleted receptors, it acts as a strong agonist of the T903-Rhoc [21].
  • Valine metabolism was investigated in five normal and three nondialyzed chronically uremic subjects eating 40 +/- SEM 1 and 53 (range 40 to 80) protein diets respectively, in a metabolic research unit [22].
  • The integrin-binding motifs RGD and ECD, present in the pro- and in mature forms of cathepsin X, respectively, suggest that this enzyme might have a function in cell signaling and adhesion [23].
  • In this paper, we use N-pentafluorobenzoylmethionylglycine-N-hydroxysuccinimide ester, our first GC-ECD release tag, to determine thyroxin in serum by a method called "labeling analysis," which involves the principle of isotope-derivative analysis [24].
  • A variety of 99mTc-labelled agents is now available or in clinical evaluation for the study of brain perfusion (99mTc-labelled HMPAO, ECD, MRP20), myocardial perfusion (99mTc-labelled MIBI, teboroxime and phosphines) and renal function (99mTc-MAG3, 99mTc-L,L-EC) [25].

Physical interactions of SHFM1

  • DSS1 is an evolutionarily conserved acidic protein that binds to BRCA2 [4].

Other interactions of SHFM1

  • Clinical features were variable, but limited to the four limbs unlike SHFM1, SHFM4 and SHFM5 [17].
  • It therefore appears that the Korean SHFM may be caused by mutation of SHFM3 [17].
  • We report the mapping of SHFM3 to chromosome 10q25 in two large SHFM families of French ancestry (Zmax for the combined families = 6.62 at theta = 0 for marker AFM249wc5 at locus D10S222) [1].
  • We found that essentially all BRCA2 in human cell lines is associated with DSS1 [4].
  • BRCA2-RAD51-DSS1 interplay examined from a microbial perspective [26].

Analytical, diagnostic and therapeutic context of SHFM1


  1. Refined mapping of a gene for split hand-split foot malformation (SHFM3) on chromosome 10q25. Raas-Rothschild, A., Manouvrier, S., Gonzales, M., Farriaux, J.P., Lyonnet, S., Munnich, A. J. Med. Genet. (1996) [Pubmed]
  2. Split hand/split foot malformation with hearing loss: first report of families linked to the SHFM1 locus in 7q21. Tackels-Horne, D., Toburen, A., Sangiorgi, E., Gurrieri, F., de Mollerat, X., Fischetto, R., Causio, F., Clarkson, K., Stevenson, R.E., Schwartz, C.E. Clin. Genet. (2001) [Pubmed]
  3. Bilateral complete radioulnar synostosis associated with ectrodactyly and sensorineural hearing loss: a variant of SHFM1. Debeer, P., Vandenbossche, L., de Ravel, T.J., Desloovere, C., De Smet, L., Huysmans, C., Thoelen, R., Vermeesch, J., Van de Ven, W.J., Fryns, J.P. Clin. Genet. (2004) [Pubmed]
  4. DSS1 is required for the stability of BRCA2. Li, J., Zou, C., Bai, Y., Wazer, D.E., Band, V., Gao, Q. Oncogene (2006) [Pubmed]
  5. Tetrahydroaminoacridine modulates technetium-99m labelled ethylene dicysteinate retention in Alzheimer's disease measured with single photon emission computed tomography imaging. Riekkinen, P., Kuikka, J., Soininen, H., Helkala, E.L., Hallikainen, M., Riekkinen, P. Neurosci. Lett. (1995) [Pubmed]
  6. Patterns of single photon emission tomography (SPECT) among patients with dementia in the memory clinic at Siriraj Hospital. Nako, A., Siritho, S., Chotinaiwattarakul, W., Ratanamart, V., Udompunthuruk, S., Jamjumrus, P., Senanarong, V. Journal of the Medical Association of Thailand = Chotmaihet thangphaet (2006) [Pubmed]
  7. Low androgen levels induce the development of androgen-hypersensitive cell clones in Shionogi mouse mammary carcinoma cells in culture. Labrie, F., Veilleux, R., Fournier, A. J. Natl. Cancer Inst. (1988) [Pubmed]
  8. Non-adrenergic, non-cholinergic nervous system and overnight airway calibre in asthmatic and normal subjects. Mackay, T.W., Fitzpatrick, M.F., Douglas, N.J. Lancet (1991) [Pubmed]
  9. p63 Gene mutations in eec syndrome, limb-mammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation. van Bokhoven, H., Hamel, B.C., Bamshad, M., Sangiorgi, E., Gurrieri, F., Duijf, P.H., Vanmolkot, K.R., van Beusekom, E., van Beersum, S.E., Celli, J., Merkx, G.F., Tenconi, R., Fryns, J.P., Verloes, A., Newbury-Ecob, R.A., Raas-Rotschild, A., Majewski, F., Beemer, F.A., Janecke, A., Chitayat, D., Crisponi, G., Kayserili, H., Yates, J.R., Neri, G., Brunner, H.G. Am. J. Hum. Genet. (2001) [Pubmed]
  10. Split-hand/split-foot malformation is caused by mutations in the p63 gene on 3q27. Ianakiev, P., Kilpatrick, M.W., Toudjarska, I., Basel, D., Beighton, P., Tsipouras, P. Am. J. Hum. Genet. (2000) [Pubmed]
  11. Fine mapping of the split-hand/split-foot locus (SHFM3) at 10q24: evidence for anticipation and segregation distortion. Ozen, R.S., Baysal, B.E., Devlin, B., Farr, J.E., Gorry, M., Ehrlich, G.D., Richard, C.W. Am. J. Hum. Genet. (1999) [Pubmed]
  12. Influence of converting enzyme inhibition on isoflurane-induced hypotension for cerebral aneurysm surgery. Van Aken, J., Leusen, I., Lacroix, E., De Somer, A., Rolly, G., Calliauw, L. Anaesthesia. (1992) [Pubmed]
  13. Pathophysiology of brain ischemia as it relates to the therapy of acute ischemic stroke. Lassen, N.A. Clinical neuropharmacology. (1990) [Pubmed]
  14. Statistical parametric mapping and statistical probabilistic anatomical mapping analyses of basal/acetazolamide Tc-99m ECD brain SPECT for efficacy assessment of endovascular stent placement for middle cerebral artery stenosis. Lee, T.H., Kim, S.J., Kim, I.J., Kim, Y.K., Kim, D.S., Park, K.P. Neuroradiology (2007) [Pubmed]
  15. A second autosomal split hand/split foot locus maps to chromosome 10q24-q25. Nunes, M.E., Schutt, G., Kapur, R.P., Luthardt, F., Kukolich, M., Byers, P., Evans, J.P. Hum. Mol. Genet. (1995) [Pubmed]
  16. Mouse model of split hand/foot malformation type I. Merlo, G.R., Paleari, L., Mantero, S., Genova, F., Beverdam, A., Palmisano, G.L., Barbieri, O., Levi, G. Genesis (2002) [Pubmed]
  17. Molecular genetic characterization of a Korean split hand/split foot malformation (SHFM). Kang, Y.S., Cheong, H.M., Moon, Y., Lee, I.B., Kim, S.M., Kim, H.S., Jun, S.Y., Jung, S.K., Kim, J.S., Choi, J.H., Cho, H.E., Son, J.S., Min, N.Y., Lee, K.H. Mol. Cells (2004) [Pubmed]
  18. Evidence for locus heterogeneity in human autosomal dominant split hand/split foot malformation. Palmer, S.E., Scherer, S.W., Kukolich, M., Wijsman, E.M., Tsui, L.C., Stephens, K., Evans, J.P. Am. J. Hum. Genet. (1994) [Pubmed]
  19. T lymphocyte activation state in the minor salivary glands of patients with Sjögren's syndrome. Segerberg-Konttinen, M., Bergroth, V., Jungell, P., Malmström, M., Nordström, D., Sane, J., Immonen, I., Konttinen, Y.T. Ann. Rheum. Dis. (1987) [Pubmed]
  20. Discrepancies in upper and lower limb patterning in split hand foot malformation. Elliott, A.M., Reed, M.H., Roscioli, T., Evans, J.A. Clin. Genet. (2005) [Pubmed]
  21. Calindol, a positive allosteric modulator of the human Ca(2+) receptor, activates an extracellular ligand-binding domain-deleted rhodopsin-like seven-transmembrane structure in the absence of Ca(2+). Ray, K., Tisdale, J., Dodd, R.H., Dauban, P., Ruat, M., Northup, J.K. J. Biol. Chem. (2005) [Pubmed]
  22. Valine metabolism in normal and chronically uremic man. Jones, M.R., Kopple, J.D. Am. J. Clin. Nutr. (1978) [Pubmed]
  23. Carboxypeptidase cathepsin X mediates beta2-integrin-dependent adhesion of differentiated U-937 cells. Obermajer, N., Premzl, A., Zavasnik Bergant, T., Turk, B., Kos, J. Exp. Cell Res. (2006) [Pubmed]
  24. Release tags: a new class of analytical reagents. Joppich-Kuhn, R., Joppich, M., Giese, R.W. Clin. Chem. (1982) [Pubmed]
  25. Radiopharmaceuticals: state of the art. Verbruggen, A.M. European journal of nuclear medicine. (1990) [Pubmed]
  26. BRCA2-RAD51-DSS1 interplay examined from a microbial perspective. Kojic, M., Holloman, W.K. Cell Cycle (2004) [Pubmed]
  27. Frequency of genomic rearrangements involving the SHFM3 locus at chromosome 10q24 in syndromic and non-syndromic split-hand/foot malformation. Everman, D.B., Morgan, C.T., Lyle, R., Laughridge, M.E., Bamshad, M.J., Clarkson, K.B., Colby, R., Gurrieri, F., Innes, A.M., Roberson, J., Schrander-Stumpel, C., van Bokhoven, H., Antonarakis, S.E., Schwartz, C.E. Am. J. Med. Genet. A (2006) [Pubmed]
  28. Physical mapping of the split hand/split foot locus on chromosome 7 and implication in syndromic ectrodactyly. Scherer, S.W., Poorkaj, P., Massa, H., Soder, S., Allen, T., Nunes, M., Geshuri, D., Wong, E., Belloni, E., Little, S. Hum. Mol. Genet. (1994) [Pubmed]
  29. Prevalence of acid reflux in functional dyspepsia and its association with symptom profile. Tack, J., Caenepeel, P., Arts, J., Lee, K.J., Sifrim, D., Janssens, J. Gut (2005) [Pubmed]
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