대한임상검사학회지 : 42권제3호, 111-1115, 2010 ISSN 1738-3544 터너증후군의심환자에서 2 개의 SRY 유전자발현 1 예 동강대학임상병리과 박상묵ㆍ김윤식 A Case of Two SRY Genes in a Tuner's Syndrome Feature Sang-Muk Park and Yoon-Sik Kim Department of Biomedical Laboratory Science, Dongkang College University, Gwangju 500-714, Korea A 15-year-old female with primary amenorrhea and Tuner's syndrome feature was referred for a chromosome analysis. The karyotype of the patient was 45,X/46,X,der(Y) mosaicism under initial GTG-banding analysis. Fluorescence in situ hybridization (FISH) analysis with probe for CEP X probes and SRY probe (Vysis, Inc. Downers Grove, IL 60515, USA) was carried out. This probe is direct labeled with SpectrumOrange (SRY, Yp11.3) and is available as a single probe or mixed with the CEP X SpectrumGreen probe. SRY SpectrumOrange/CEP X SpectrumGreen hybridized to a specimen obtained from an two isodicentric Y chromosomes. The karyotype of the patient was ish Xcen(DXZ1x1)/Xcen(DXZ1x1), Yp11.3(SRYx2) by using FISH. This karyotype was considered a variant of Tuner syndrome with mixed gonadal dysgenesis (MGD), male pseudohermaphroitism (MPH) and apparently normal male Received 29, OCT 2010 / Returned for modification 1, DEC 2010 / Accepted 23, DEC 2010 Key Words : Primary amenorrhea, Turner s syndrome, SRY gene, FISH. Ⅰ. 서론 터너증후군 (Tuner syndrome) 은염색체검사핵형에의해진단되어지는유전질환으로단신, 성부전증등다양한형태의신체적인표현형을유발하는것으로알려져있다 (Ogata와 Matsuo, 1995). 터너증후군은염색체검사에서 45,X, 46,X,del(X), 46X,i(X) 등과섞임증 (mosaicism) 현상까지매우다양한형태의분포를나타 교신저자 : 김윤식, ( 우 ) 500-714, 광주광역시북구동문로 160 동강대학임상병리과 Tel : 062-520-2524, 010-9897-2982 E-mail : kys2982@naver.com 내고있다 (Kim 등, 2004). 그러나터너증후군의심환자에서 iso(y) 가관찰되는예의보고는매우적다 (Kohn 등, 1997; Godoy Assumpção 등, 2000; Stankiewicz 등, 2001). 특히 SRY(sex determining region of the Y chromosome) 유전자가여성에게서발견된경우는외부생식기가애매하거나불완전한남성화또는완전한여성화로되어나타나는거짓남녀중간몸증 (male pseudohermaphroditism; MPH) 등의다양한표현형으로나타나는것으로알려져있다 (Michiels 등, 1984; Park 등, 2008). 이번증례에서 1차성무월경과터너증후군이의심되어내원한 15세여학생에게세포유전학적검사와형광제자리부합법 (Fluorescence in situ hybridization; FISH) 검사를병행하여검사를실시한결과 Y 염색체에서두 111
Park SM. and Kim YS. A Case of Two SRY Genes in a Tuner's Syndrome Fig 1 The chromosomal study of the cultured peripheral blood of the proband revealed 46,XY(left) and 45,X(right) chromosome pattern by GTG-banding. 개의 SRY 유전자를관찰할수있었으며, 이는터너증후군환자에서매우드문경우이기에문헌조사와함께보고하는바이다. II. 증례 1. 대상환자환자는 15세여아로내원당시초경이없는 1차성무월경과꽃가루에대한심한알레르기증상을호소하며내원하였으며, 가족력은 2녀중차녀로양친부모와첫째아이에게는특이소견이발견되지않았다. 2. 진찰및임상검사소견내원당시성장속도가 1년에 3~4 cm으로외형상터너증후군의표현형을보였으며, 신장은 127.9 cm와체중은 24.9 kg을보였고, 혈압, 맥박, 체온호흡수등은정상증상을보였다. 외음부소견은정상여성의소견을보였으며초음파검사결과자궁모양은확실하게구별되지않았다. MRI 검사결과오른쪽과왼쪽난소부위에서흔적생식샘 (streak gonad) 이관찰되었다. 3. 검사소견성선과관련된내분비호르몬검사에서 FSH 71.3 miu/ml, LH 15.4 miu/ml, E 2 34.9 pg/ml, testosterone 0.25 ng/ml, PRL 10.9 ng/ml을보였다. GTG-분염법을이용한세포유전학적염색체검사를실시한후핵형분석결과분석가능한 122개세포중에 서 45,X 세포 70개와 46,XY 세포 52개가관찰되었다 (Fig. 1). Fig. 2와같이 XY염색체에서 CEP X probes and SRY probe(vysis, Inc. Downers Grove, IL60515, USA) 를이용하여형광제자리부합법으로검사를실시한결과 SRY 유전자가 2개관찰되어같은팔염색체 (isochromosome) Y로확인되었다. 최종염색체에의한염색체검사핵형은 45,X[70]/ 46,XY[52],mosaicism이었으며, 형광제자리부합법에의한핵형은 ish Xene(DXZ1x1)[233]/Xcen(DXZ1x1),Yp11.3 (SRYx2)[87] 로확인되었다 (Fig. 3). III. 고찰 Sinclair 등 (1990) 은남성을결정하는인자가 Y 성염색체의단완에존재하며, 고환분화에필요한정보를지니는고환결정인자를확인하여보고하였는데이를 SRY(sex-determining region Y chromosome) 유전자라고명명하였다. 따라서 SRY 유전자는성선을고환으로분화하여남성으로결정하는가장중요한역할을하는유전자라고알려져있으며, 그외에도 SF-1(steroidogenic factor-1), SOX-9(SRY-box-9), DAX-1(dosage-sensitive sex reversal region on X) 및일부상염색체등도관련이있는것으로보고되고있다 (Müller 등, 1992; Harley 등, 2002; Wallis 등, 2008). 여성의경우는 SRY 유전자가존재하지않아성선이고환대신난소로분화되는것으로알려져있다. 따라서 SRY 유전자에이상이있거나 X 염색체로전이한경우각각 46,XY 여성, 46,XX 112
Korean J. Clin. Lab. Sci. 42(3):111-115, 2010 남성과같은성분화장애를유발할수있다. 성분화이상의대표적인표형의이상으로알려진터너증후군은 Ford 등 (1959) 에의해 X 염색체이상질환으로진단된이래로많은연구자들에의해매우다양한형태의신체적표현형을발현되는것으로알려졌다 (Rovet, 1993; Kim 등, 2004; Sybert와 McCauley, 2004; Doerr 등, 2005). 대표적증상은성선부전증, 단신등다양한신체적유전증후군를보인다. 또한세포유전학적검사결과도 X 염색체두개중하나가부족한 45,X 염색체핵형을보이는경우를비롯하여나머지하나에서팔이결손된 del(x), 같은팔염색체 i(xq) 그리고섞임증까지매우다양한형태의핵형분포를나타내고있으며, 이러한형태에따라터너증후군환자의표현형도다양한표현양상을보이는것으로나타나고있다. 특히여성에게서 SRY 유전자가발견된경우는외부생식기가애매하거 Fig 3 FISH with probe for CEP X probes and SRY (Yp113) probe. This probe is direct labeled with SpectrumOrange (SRY, Yp113) and is available as a single probe or mixed with the CEP X SpectrumGreen probe (Vysis, Inc Downers Grove, IL, USA). Fig 2 The SRY gene is located within 10 kb of the pseudoautosomal region of Yp. The LSI SRY probe is useful in detecting deletions of SRY or presence of the gene in rearrangements involving the X chromosome, autosomes and marker chromosomes. The LSI SRY DNA FISH probe is an approximately 120 kb probe specific to the SRY gene and flanking sequences. This probe is direct labeled with SpectrumOrange and is available as a single probe or mixed with the CEP X SpectrumGreen probe. 113
Park SM. and Kim YS. A Case of Two SRY Genes in a Tuner's Syndrome 나불완전한남성화또는완전한여성화로되어거짓남녀중간몸증등다양한표현형을나타내는것으로알려져있다 (Michiels 등, 1984). 특히남성화현상으로고환이발생되는경우악성종양으로발전할수있으므로외과적수술방법으로제거해야하는것으로알려져있다 (Nihoul-Fékété 등, 2006). 이번터너증후군의심환자의경우는 X 염색체불완전한분화현상으로사료되므로계속적인추적관찰을통해치료와유전상담을실시하는것이필수적이라하겠다. 참고문헌 1. Doerr HG, Bettendorf M, Hauffa BP, Mehls O, Partsch CJ, Said E, Sander S, Schwarz HP, Stahnke N, Steinkamp H, Ranke MB. Uterine size in women with Turner syndrome after induction of puberty with estrogens and long-term growth hormone therapy: results of the German IGLU Follow-Up Study 2001. Hum Reprod 20:1418-1421, 2005. 2. Ford CE, Jones KW, Polani PE, de Almeida JC, Briggs JH. A sex-chromosome anomaly in a case of gonadal dysgenesis(turner's syndrome). Lancet 1(7075):711-713, 1959. 3. Godoy Assumpção J, Hackel C, Marques-De-Faria AP, Palandi de Mello M. Molecular mapping of an idic(yp) chromosome in an Ullrich-Turner patient. Am J Med Genet 91:95-98, 2000. 4. Harley VR. The molecular action of testisdetermining factors SRY and SOX-9. Novartis Found Symp 244:57-66, 2002. 5. Kim YS, Kee WJ, Back HK, Lee SH, Shin JH. Analysis of Cytogenetics Diagosis: From 30Years Experience at Kwangju Christian Hospital. J Kor Clinical Lab Sciences 36(2):205-209, 2004. 6. Kohn B, Kleyman SM, Conte RA, Macera MJ, Glassberg K, Verma RS. Characterization of an isodicentric Y-chromosome for the long arm in a newborn with mixed gonadal dysgenesis. Ann Genet 40:10-13, 1997. 7. Michiels I, Peperstraete L, De Wever I, Gruwez JA. Inguinal hernia repair leading to the diagnosis of internal male pseudohermaphroditism. Acta Chir Belg 84(4):255-258. 1984. 8. Müller J, Schwartz M, Skakkebaek NE. Analysis of the sex-determining region of the Y chromosome (SRY) in sex reversed patients: point-mutation in SRY causing sex-reversion in a 46,XY female. J Clin Endocrinol Metab 75(1):331-333, 1992. 9. Nihoul-Fékété C, Thibaud E, Lortat-Jacob S, Josso N. Long-term surgical results and patient satisfaction with male pseudohermaphroditism or true hermaphroditism: a cohort of 63 patients. J Urol 175(5):1878-1884, 2006. 10. Ogata T, Matsuo N. Turner syndrome and female sex chromosome aberrations: deduction of the principal factors involved in the development of clinical features. Hum Genet 95:607-629, 1995. 11. ParK SH, Shim SH, Chin MU, Kang SJ, Bae SM, Sohn SM, et al. Pseudoisodicentric X chromosome in a female with primary amenorrhea. J Kor Soc Medical Genetics. 5(1):61-64, 2008. 12. Rovet JF. The psychoeducational characteristics of children with Turner syndrome. J Learn Disabil 26(5):333-341, 1993. 13. Sinclair AH, Berta P, Palmer MS, Hawkins JR, Griffiths BL, Smith MJ, Foster JW, Frischauf AM, Lovell-Badge R, Goodfellow PN. A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature 346(6281):240-244, 1990. 14. Stankiewicz P, Hélias-Rodzewicz Z, Jakubów- Durska K, Bocian E, Obersztyn E, Rappold GA, 114
Korean J. Clin. Lab. Sci. 42(3):111-115, 2010 Mazurczak T. Cytogenetic and molecular characterization of two isodicentric Y chromosomes. Am J Med Genet 101:20-25, 2001. 15. Sybert VP, McCauley E. Turner's syndrome. N Engl J Med 351(12):1227-1238, 2004. 16. Wallis MC, Waters PD, Graves JA. Sex determination in mammals-before and after the evolution of SRY. Cell Mol Life Sci 65(20):3182-3195, 2008. 115