5727 JMed Genet 1995;32:572-575 Chromosomal localisation of a Y specific growth gene(s) J Med Genet: first published as 10.1136/jmg.32.7.572 on 1 July 1995. Downloaded from Tsutomu Ogata, Keiko Tomita, Akiko Hida, Nobutake Matsuo, Yutaka Nakahori, Yasuo Nakagome Abstract apparently large Yq terminal deletions are in- Although a Y specific growth gene(s) has variably sterile and occasionally have short been postulated in the Yqll region, the stature.24 However, since correlations between precise location has not been determined. genotype and stature have not been properly To localise the growth gene(s), we cor- examined, the precise location ofthe Y specific related genotype with stature in 13 Jap- growth gene(s) has not been determined. anese and four European non-mosaic In this paper, we attempt to localise the Y adult male patients with a partial Yq de- specific growth gene(s) on the basis of geno- letion. Fourteen patients preserving the type-phenotype correlations in patients with region between DYSll and DYS246 did Yq - chromosomes. not have short stature (11 Japanese, 165-180 cm; three Europeans, 165-173 cm) whereas the remaining three patients with Methods SELECTION OF PATIENTS the region deleted had short stature (two The patients analysed in the present study were Japanese, both 159 cm; one European, collected from a large series ofinfertile Japanese 157 cm). The results suggest that the region males ascertained from 1988 to 1993. The defined by DYS1I at interval 5C and by selection criteria used were: (1) measurement DYS246 at interval SD may be the critical of height between 20 and 50 years of age; region for the Y specific growth gene(s). (2) lack of associated disorders or therapeutic interventions that may affect stature; (3) ab- (J'Med Genet 1995;32:572-575) sence of demonstrable mosaicism; (4) lack of autosomal or X chromosomal abnormalities; The Y chromosome carries a Y specific growth (5) confirmation of a partial Yq deletion by gene(s) that significantly augments adult height molecular studies; and (6) exclusion of i(Yp) independently of the effect of gonadal sex ster- or idic(Y)(qll) chromosomes which are as- oids. This hypothesis is primarily based on sociated with two copies of a pseudoautosomal the white adult height comparisons between growth gene(s),5 but are not necessarily dis- patients with pure XY gonadal dysgenesis and tinguishable from non-fluorescent Yq- chro- http://jmg.bmj.com/ those with pure XX gonadal dysgenesis (172.0 mosomes by standard cytogenetic studies.6 In (SD 7.0) cm, n=24 v 164.3 (SD 7.7) cm, n= addition, male patients satisfying the above 22, p<0.01), between patients with complete selection criteria were taken from published testicular feminisation syndrome and normal reports. females (172.2 (SD 6.5)cm, n=23, v 162.2 (SD 6.0) cm, British standard, p<0.01), and HEIGHT ASSESSMENT between normal males and XX males (174.7 The adult heights of Japanese patients were on October 2, 2021 by guest. Protected copyright. (SD 6.7) cm, British standard v 166.4 (SD assessed by the Japanese height standards based n = In the three com- 7.4) cm, 33, p<0.01)."2 on the 1980 national survey (169.7 (SD 5.6) cm the sex chromosome is parisons, complement for males and 157.0 (SD 5.0) cm for females), Department of different but the effect of bioactive gonadal sex and those of white patients taken from pub- Paediatrics, Keio steroids is comparable. Furthermore, on the University School of basis of the adult height differences indicated lished reports were assessed by the British Medicine, 35 height standards reported by Tanner et al7 Shinanomachi, by the three comparisons, it has been assumed that the Y increases the (174.7 (SD 6.7) cm for males and 162.2 (SD Shinjuku-ku, Tokyo specific growth gene(s) 6.0) cm for females). When possible, adult 160, Japan adult height by 8-10 cm and thus accounts for T Ogata height was compared between the patient and N Matsuo about two-thirds of the sex difference in mean his normal sib(s) with a similar genetic and adult height (about 13 cm).`- The remaining environmental background. To allow for height Department of Human between sexes has been adult height difference comparisons between different races and be- Genetics, University of the notion that testicular an- Tokyo, 7-3-1 Hongo, explained by tween different standard deviation to increase adult sexes, height Bunkyo-Ku, Tokyo drogens have the potential score (SDS) was obtained using the equation: 113, Japan 3-5 cm while ovarian oestrogens have height by height SDS = (X - M)/SD, where X is an in- K Tomita no major effect on adult height.'-3 A Hida dividual person's height and M and SD are the has been as- Y Nakahori The Y specific growth gene(s) mean and the standard deviation of the normal Y Nakagome signed to Yqll, proximal to the gene(s) for population, respectively. on Correspondence to: spermatogenesis, the basis of karyotype- Dr Ogata. phenotype correlations.4 Non-mosaic adult Received 5 December 1994 male patients with apparently small Yq terminal MOLECULAR STUDIES Revised version accepted for not DNA was extracted from publication 15 February deletions are frequently sterile but do Genomic peripheral 1995 usually have short stature, whereas those with leucocytes of each Japanese patient and was Chromosomal localisation of a Y specific growth gene(s) 573 1 2 3 4 5 L-( < o~ a) - HIC | II 1 (O -4.n C _s n X E a >- ) mm:^> t en ) 0 LO OOO O-O <00 0CY) 000000000',- m >. > > >->-r- r- LLU- X N eeOM) U.rW> en en N _n.- -4-X < x LLx x> > > > > > 2 > > > > >--> > > > > > > >- J Med Genet: first published as 10.1136/jmg.32.7.572 on 1 July 1995. Downloaded from (1--N00000000<:000c0 000 0000001C l I I Figure 1 An example of Case 1 46, XY ._-M 1 180 +1.84 discrimination between 2 46,XY 1 175 +0.95 non-fluorescent Yq - 3 46,XY ~~mEI~-- 1 173 +0.59 chromosomes and i(Yp) or 4 46,XY ii-ii i ~~~- -m 171 +0.23 5 46,XY 171 +0.23 idic(Y)(qll) chromosomes. - mu - mum * - ~~~~~---m Shown are TaqI digests 6 46,XY 1 165 -0.84 7 46, X,Yq-(nf) 69 -0.13 hybridised with 47z 8 46, X,Yq-(nf) ~mI--------- 175 +0.95 Japanese defining an Xq-Yp 9 46,XY 173 +0.59 homologous locus 10 46, X,Yq-(nf) ~~IE ~ ~ M 172 +0.41 (DXYS5) (lane 1: control 11 46,X.Yq-(nf) 176 +1.13 male; lanes 2, 3, and 5: 12 46, X,Yq-(nf) 159 -1.91 infertile male patients with 13 46,X.Yq-(nf) 159 -1.91 46,X, + mar; lane 4: XX male). The intensity ratio 14 46, X,Yq-(nf) 173 -0.26 between the X specific and 15 46. X,Yq-(nf) - 2 ** * *- - -- 172 -0.41 i Y specific bands is 16 46, X,Yq-(nf) * ~ ~~~~~~~* * *- 165 -1.46 Whites comparable between lanes 17 46, X,Yq- 157 -2.661i 1, 2, and 3, indicating that DXYSSY is present in a single copy in patients 2 I. and 3. Thus, the two ,, patients were interpreted as having a 46,X, Yq- karyotype and were u a 0 - included in the present fMI*l I Iw11 IH study (cases 11 and 12 in fig 2). By contrast, the comparison of band intensity between lanes 1 and 5 implies that DXYSSY is present in two Case 11 - - - - copies in patient 5. Thus, the patient was regarded as 137 - - -X having a 46,X,i(Yp) or a 46,X,idic(Y) (qll) karyotype and was excludedfrom the present study. The comparison of Critical region for band intensity between a Y specific growth gene(s) lanes 1 and 4 is consistent with the XX male patient Figure 2 Genotype-phenotype correlations of a Y specific growth gene(s) in non-mosaic patients with Yq - having two copies of chromosomes. The case numbers correspond to those in the table. Karyotype (nf= non-fluorescent), height, and height DXYSSX. SDS (standard deviation score) are shown for each case. The black segments represent the positive loci confirmed by http://jmg.bmj.com/ molecular studies, the striped segments represent the presumed positive loci inferredfrom interpolation or cytogenetic findings, the minus symbols represent the negative loci confirmed by molecular studies, the open segments represent the presumed negative loci inferredfrom interpolation or cytogenetic findings, and the asterisks represent the dosage unknown loci. The critical region for a Y specific growth gene(s) is shown by the arrow. analysed by Southern blotting and the poly- 52d (DYF27/A-C), 87-4 (AMGL), 12f3 on October 2, 2021 by guest. Protected copyright. merase chain reaction (PCR). For Southern (DYSl1), 87-28 (DYS140), 87-26 (DYS139), blot analysis, genomic DNA was digested with 87-31 (DYS134), 87-19 (DYS132), 87-6 EcoRI, TaqI, or StuI, and was hybridised with (DYS135), 49f (DYSI), and pHY10 the following probes: pDP1007 (ZFY), 47z (DYZ1).5-" For PCR analysis, genomic DNA (DXYS5Y), 87-27 (DXYS73Y), 50f2 (DYS7/ was amplified with following primers: PABA/ A-E), 87-17 (DYS131/A,B), 87-7 (DYS13O), PABB/PABC (PABX/PABY), SRY-lF/SRY-2R (SRY), sY78 (DYZ3), sY81 (DYS271), sY82 (DYS272), sY83 (DYSli), sY84 (DYS273), Adult male patients used in the present study sY87 (DYS275), sY86 (DYS 148), sY85 Case Reference (DY274), sY165 (DYS246), sY90 (DYS278), sY91 (DYS 136), sY94 (DYS279), and sY95 Japanese 1 Unpublished 2 Nagafuchi et all5 (patient No 1411) (DYS280).