9J Med Genet 1993 30: 918-922

Chromosomal localisation of a gene(s) forTurner stigmata on Yp

Tsutomu Ogata, Chris Tyler-Smith, Stuart Purvis-Smith, Gillian Turner

AbstractAlthough recent cytogenetic and molecu-lar studies in patients with Turner stig-mata are consistent with a gene(s) forTurner stigmata being present on bothXp and Yp, the precise location has notbeen determined. In this report, we de-scribe a phenotypically female infantwith Turner stigmata and a partial Ypdeletion and review genotype-phenotypecorrelations of the putative Turnergene(s) in non-mosaic patients with Ychromosome rearrangements resultingfrom chromosomal breakage at Yp or Yc(pericentromeric region). The results in-dicate that the putative Turner gene(s)on Yp is located in the Y specific regionfrom interval lAlA to interval 2B. Inaddition, assessment of ZFX/ZFY andRPS4X/RPS4Y in the context of theTurner gene(s) suggests that ZFX/ZFYrather than RPS4X/RPS4Y could be acandidate gene for the Turner stigmata.(J Med Genet 1993;30:918-22)

Human MolecularGenetics Laboratory,Imperial CancerResearch Fund,London, UK.T Ogata

CRC ChromosomeMolecular BiologyGroup, Department ofBiochemistry,University of Oxford,UK.C Tyler-Smith

Cytogenetics Unit,The Prince of WalesChildren's Hospital,Randwick, Australia.S Purvis-Smith

Department ofMedical Genetics, ThePrince of WalesChildren's Hospital,Randwick, Australia.G Turner

Correspondence toDr Ogata, Department ofPaediatrics, Keio UniversitySchool of Medicine, 35Shinanomachi, Shinjuku-ku,Tokyo 160, Japan.Received 23 February 1993.Revised version accepted1 June 1993.

Turner syndrome is associated with character-istic somatic features such as webbed neck, lowposterior hair line, lymphoedema, and cubitusvalgus.' 3 Since such Turner stigmata are fre-quently manifested by patients with 45,X,46,X,Xp-, and 46,X,i(Xq),3 it has been sug-

gested that Xp carries a gene(s) for Turnerstigmata which escapes X inactivation.4 Inaddition, Turner stigmata have also beenreported in patients with 46,X,Yp-,3 indicatingthat Yp also contains a gene(s) for Turnerstigmata.4 These findings imply that thegene(s) for Turner stigmata is shared by Xpand Yp, and that haploinsufficiency of thegene(s) results in the development of Turnerstigmata.4 Although patients with 46,X,Xq-also sometimes have Turner stigmata,3 thiscould be explained by assuming that the puta-tive Turner gene(s) on Xp escapes X inactiva-tion on normal X chromosomes but is prone toundergo X inactivation on structurally abnor-mal X chromosomes.5The putative Turner gene(s) has been

located in the sex specific regions of Xp andYp.4 Although genes in the pseudoautosomalregion (PAR) share homology between the Xand the Y chromosome and are expected to

escape X inactivation, genetic evidence cur-

rently available argues against the Turnergene(s) being present in the PAR. It has beenshown by cytogenetic and molecular studiesthat the putative Turner gene(s) on Xp ispresent in the middle part of Xp.45 It has alsobeen shown that sex reversed patients with46,XY caused by an abnormal Xp;Yp inter-

change have Turner stigmata in the presenceof two doses of the PAR.6 However, the preciselocation of the Turner gene(s) in the sex speci-fic regions has not been determined.

In this report, we describe a patient withTurner stigmata and a partial Yp deletion, andreview genotype-phenotype correlations of theputative Turner gene(s) on Yp. In addition,the possibility that ZFX/ZFY and RPS4X/RPS4Y could be the Turner gene(s) is dis-cussed.

Case reportThis phenotypic female infant was the 3200 gproduct of an uncomplicated term pregnancyand delivery. Physical examination at 1 monthof age showed webbed neck, low posterior hairline, lymphoedema of the hands and feet,redundant skin folds, and hypoplastic toenails.External genitalia were completely feminine,and an abdominal ultrasound indicated thepresence of a normal uterus and a gonadalstructure in the place of the left ovary. Cardiacevaluation showed a small patent ductus arter-iosus. The subsequent clinical course wascompletely uneventful, and her length was82 cm at 18 months of age (50th centile).On the basis of the above findings, she wasdiagnosed as having characteristic Turnerstigmata, but was free from apparent growthfailure.The non-consanguineous parents were

clinically normal. The younger brother had alarge right sided cystic hygroma at birth whichwas surgically removed at 5 months of age.However, he had no other Turner stigmata,including webbed neck, and exhibited normalmale sex development and growth pattern.

CYTOGENETIC STUDIESChromosome analysis was performed on 170peripheral blood lymphocytes of the patientand on 15 lymphocytes of the younger brotherand the parents, using G banding, C banding,and N banding (Ag-NOR).The karyotypes of the patient, the younger

brother, and the father were 46,X,Yqs with noevidence of mosaicism. No structural abnor-mality was detected in the Y chromosomeshort arm of the patient. The mother's karyo-type was 46,XX.

MOLECULAR STUDIESGenomic DNA was extracted from peripheralleucocytes of the patient, the father, and nor-mal subjects, and digested with EcoRI, TaqI,and SstI. Southern transfer, probe hybridisa-

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Chromosomal localisation of a gene (s) for Turner stigmata on Yp

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Figure 1 Southern blot analysis (F=father, P= patient, Y= normal female, 3= normal male). (1) EcoRI digestshybridised with 29C1 (DXYS14). The probe detects bands specific to the patient and to the father, together withthose shared by them. (2) TaqI digests hybridised with 19B (MIC2). RFLP pattern shows the presence of twocopies of MIC2 in the patient. (3) SstI digests hybridised with HfO.2 (PABX/PAB Y). PABY is absent in thepatient, although PABX is present. (4) EcoRI digests hybridised with pY53.3 (SR Y). The patient is negative forSR Y. (5) EcoRI digests hybridised with HfO.2 (PABX/PAB Y) (top panel), MIA (DXS31) (second panel),pG15 (DXYS61) (third panel), and probe for autosomal TK gene as an internal control (bottom panel) (samefilter; NB, the EcoRI filter is different from that used for 29C1, p Y53.3, 50f2, and 52d). Band intensity ratios are(F, P, Y, Y, X, ,3): PAB/TK (153, 167, 1 63, 1 45, 1 40, 152); DXS31/TK (015, 018, 0-35, 030, 012,0 09); and DXYS61/TK (0-47, 0-51, 1-15, 1 21, 1 05, 0-91). The results indicate that, in both the patient and thefather, PAB is present in two copies and DXS31 and DXYS61 are present in a single copy. (6) EcoRI digestshybridised with 50f2 (DYS7). DYS7/A and DYS7/B are absent in the patient. (7) EcoRI digests hybridised with52d (DYF27). The patient is negative for D YF27/B. Intensity ratio between DYF27/C band and the X specificband (the second upper band) is 1 39 for the father, 0-74 for the patient, and 1 65 and 1 76 for the two controlmales, implying that one copy of D YF27/C in interval 3 is deleted whereas the other copy in interval 4 is preservedin the patient.

tion, and autoradiography were carried out bystandard methods. The probes used were: (1)PAR: 29C1 (DXYS14), 113D (DXYS15), 601(DXYS17), 19B (MIC2), and HfO.2 (PABX/PABY); (2) X specific region at Xp22.3: MIA(DXS31); (3) Y specific euchromatic region:pY53.3 (SRY), 27a (DYS104), GMGY3(DYS13), pMF-1/pPB (ZFY), 47Z(DXYS5Y), 50f2 (DYS7), 52d (DYF27),pDP34 (DXYS1Y), and p2F(2) (DYS25); and(4) Xqter-Yqter region: pG15 (DXYS61).(The references for the probes have beenshown in the reports of Davies et a17 andWeissenbach and Goodfellow.8) Probe 50f2detects five Y specific EcoRI fragments desig-nated A, B, C, D, and E. Probe 52d detectsthree Y specific EcoRI fragments designatedA, B, and C; the C fragment is a doublet,composed of one copy from interval 3 and theother copy from interval 4 (Tyler-Smith,unpublished data). Probe pG15 detects anXqter-Yqter homologous locus. The copynumber ofX-Y homologous loci, DXS31, andDYF27/C was determined by the pattern ofrestriction fragment length polymorphisms orby the comparison of band intensity measuredby a laser densitometer (Ultroscan, LKB).

Representative results are shown in fig 1 and

summarised in fig 2 (case 6). In the patient, theY specific loci from interval lAlA to interval 3were deleted, whereas those assigned to inter-val 4 were preserved. Although PABY wasabsent, PABX was present in two copies aswere other pseudoautosomal loci. DXS31 waspresent in a single copy. Both the patient andthe father had a single copy of DXYS61, asexpected from the cytogenetic findings of theYqs chromosomes.

DiscussionThe present study indicates that the Yqs chro-mosome of the patient is missing the Y specificregion from interval lAlA to interval 3, as aresult of an abnormal Xp;Yp interchange dur-ing paternal meiosis (fig 3). Although the Ychromosomal PAR is also deleted, this is com-pensated for by the translocation of the Xchromosomal PAR. These findings providefurther evidence that the putative Turnergene(s) on Yp is located in the distal part of theY specific region rather than in the PAR. Inaddition, sex reversal is explained by the dele-tion of SRY,34 and normal growth is consistentwith the pseudoautosomal growth gene(s)being present in two copies35 and gross chro-

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Figure 2 Genotype-phenotype correlations of the putative Turner gene (s) in non-mosaic patients with rearrangedY chromosomes resulting from chromosomal breakage at Yp or Yc (pericentromeric region). Age, karyotype, andphenotypic sex (F=female, M= male) are shown for each case (45,X males have unbalanced Y; autosometranslocations). References: case 1,910 cases 2 and 3,6 cases 4 and 5,10-14 case 6 [present case , case 7,151-7 case 8,1012case 9,14 18 case 10,1920 case 11,21 case 12,22 case 131023-21 case 14,1026 case 15, 102728 case 16, 13 1429 case 17,3031 and case18.32 (For cases 14, 16, and 17, unpublished data of Tyler-Smith have been included.) The Y chromosomal intervalsare based on the deletion maps reported by Vollrath et al.'° Probes and sequence tagged sites defining each locus areshown in the reports of Weissenbach and Goodfellow8 and Vollrath et al.'0 The locus order within thepseudoautosomal region (PAR) is derived from the physical map reported by Petit et al,33 and that within the Yspecific region is based on the deletion maps constructed by Vollrath et al,'0 Affara et al,'6 and Tyler-Smith(unpublished data). (However, the precise order remains to be determinedfor the intervals 2A, 2C, 3, and 4.) Forthe Y specific region, the black segments represent the positive loci confirmed by molecular studies, the stripedsegments represent the presumably positive loci inferred from interpolation or cytogenetic findings, the minus symbolsrepresent the negative loci confirmed by molecular studies, the open segments represent the presumably negative lociinferred from interpolation, cytogenetic findings, or sexual phenotype, and the asterisks represent the dosage unknownloci. The stippled segments for D YF27/C in cases 6 and 16 denote that the locus has been confirmed to be present inreduced band intensity. For the PAR, the black segments indicate the confirmed disomic loci, the striped segmentsindicate the presumably disomic loci, the minus symbols indicate the confirmed monosomic loci, the open segmentindicates the presumably monosomic locus, and the asterisks indicate the dosage unknown loci (it is uncertain whetherthe Yp- chromosomes in cases 1, 4, 5, 8, 9, and 16 are formed by abnormal Xp; Yp interchanges or by simpledeletions). The location of the putative Turner gene (s) is shown by the arrow.

mosome imbalance being absent.36 Althoughour patient inherited the satellited Y chromo-some from the father, the apparently normalphenotype of the father suggests that the struc-tural abnormality of Yqs has no phenotypiceffect.For a more precise 19.calisation of the puta-

tive Turner gene(roon Yp, it is useful toreview genotype-phenotype correlations inpersons with Y chromosome rearrangementsresulting from chromosomal breakage at Yp orYc (pericentromeric region). For this purpose,we surveyed published reports for informativepatients using the following criteria: (1) analy-sis of the rearranged Y chromosomes by mo-lecular studies; (2) absence of numerical orstructural abnormalities of the X chromosome;(3) lack of demonstrable mosaicism; and (4)description of somatic features. Consequently,a total of 18 informative patients was identified(fig 2). Before the correlations, however, twomatters should be considered, that is, thenumber of genes involved and problems inher-ent in phenotypic assessment.The number of Turner genes is unknown,

but there are some indicators. Most Turner

stigmata can be classified into three groups: (1)features attributable to lymphatic stasis, suchas webbed neck, low posterior hair line,rotated ears, lymphoedema, redundant skin,nail dysplasia, and characteristic dermatogly-phics; (2) those attributable to skeletal anomal-ies, such as short neck, micrognathia, cubitusvalgus, and short metacarpals and metatarsals;and (3) those attributable to vascular dysplasia,such as cardiac anomalies and, possibly, renalmalformations.2 Since lymphovascular andskeletal systems are derived from mesen-chyme, disruption of mesenchymal develop-ment might lead to the various Turnerstigmata. Alternatively, lymphatic malforma-tion alone'7 might cause the various Turnerstigmata. The possible contribution of lym-phatic malformation to skeletal anomalies hasbeen speculated upon.'8 In fact, skeletal anom-alies are detectable in the regions where thereis retention of lymphatic fluid. A potentialrelationship of lymphatic stasis to cardiac andrenal malformations has also been sug-gested.23940 Thus, despite the phenotypic di-versity, Turner stigmata could most simply beexplained as sequelae of an impairment of a

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921Chromosomal localisation of a gene(s) for Turner stigmata on Yp

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Figure 3 A schematic representation of the generation of the patient's Yqschromosome. White, striped, and stippled areas depict the pseudoautosomal, X specific,and Y specific regions, respectively. The area indicated by horizontal lines denotes thechromosomal satellite. The patient's Yqs chromosome was formed by an abnormalXp; Yp interchange during paternal meiosis, with the breakpoints being betweenPABX and DXS31 in the X specific region and at the border of intervals 3 and 4 inthe Y specific region. Consequently, SRY and the putative Turner gene (s) in the Yspecific region were lost, whereas the pseudoautosomal growth gene (s) was present intwo doses.

single gene that is relevant to mesenchymal or

lymphatic development. Although Shepardand Fantel" regarded hypoalbuminaemia andresultant oedema as the cause of variousfeatures, Turner stigmata have not beendescribed in subjects with hydrops fetalis re-

sulting from various conditions other thanlymphatic anomalies and sex chromosome ab-normalities, in spite of the presence of oedemaand hypoalbuminaemia.4'Problems inherent in phenotypic assessment

include the following. First, the incidence ofeach somatic feature remains only about 20 to50%, 2 implying that haploinsufficiency of theTurner gene(s) may not necessarily result inclinically discernible stigmata. Indeed,because of the highly variable phenotypic pre-

sentation, karyotyping has been suggested forany girl with unexplained short stature.'Second, conspicuous Turner features may

change with age. For example, lymphoedemais a striking feature at birth but usually re-

solves during infancy, and skeletal featuresappear to become obvious after infancy." 842Such age dependent features may be over-

looked, if not assessed at an appropriate age.

Third, specific studies such as skeletal radio-graphs and cardiac evaluation are often notperformed, so that several features may remainundetected. Fourth, although several featuressuch as high arched palate, scoliosis, and pig-mented naevi are frequently manifested byTurner patients,'2 they are not characteristicof Turner syndrome but common to variousdisorders.42 Lastly, because of the lack of ob-jective criteria, equivocal features may be diffi-cult to assess accurately, even characteristicstigmata such as webbed neck and cubitusvalgus. These caveats indicate that genotype-phenotype correlations are more reliable in

patients with characteristic Turner stigmatathan in those with no or equivocal stigmata.Genotype-phenotype correlations in 18

informative patients are shown in fig 2. Thesimplest explanation is to assume a singleTurner gene in the Y specific region fromlAlA to 2B. This location is based on theresults of cases 1 to 9. All nine females hadlymphoedema during fetal or infant life, threeof them (cases, 4, 8, and 9) exhibited skeletalmanifestations, and three of them (cases 1, 6,and 8) had cardiac or renal malformations. Itmight be possible that other Turner genes arepresent in the more proximal region. If this isthe case, a gene(s) for lymphatic developmentis located in this region. The assignment isconsistent with absent Turner stigmata incases 10 to 15, although lack of stigmata,especially in male patients with a partial auto-somal monosomy, does not necessarily implythe presence of the Turner gene(s). The resultsof cases 16 to 18 may be confounding, but theydo not provide direct evidence against theabove location. The lack of Turner features incase 16 could be explained by assuming thatexpressivity was severely reduced or that somefeatures remained undetected. Although case17 has a high arched palate, short and slightlywebbed neck, and shield chest, it is uncertainwhether such non-characteristic or equivocalmanifestations are directly caused by an im-pairment of the Turner gene(s). Rather, theycould be the result of autosomal involvement.Although case 18 has a low hair line, higharched palate, pigmented naevi, and horseshoekidney, the features also appear somewhatequivocal. In addition, latent mosaicism with a45,X cell line is possible in case 18, since thepatient has partial gonadal dysgenesis in thepresence of SRY. Furthermore, it might bepossible that, because of a cryptic complexdeletion, the Turner gene(s) is preserved incase 16 and affected in cases 17 and 18.Two genes of unknown function, ZFY27 and

RPS4Y,43 have been cloned from the region ofthe Tumer gene(s). Both genes are associatedwith the homologous genes on the X chromo-some, ZFX and RPS4X, which normallyescape X inactivation.43 Since ZFX is presentat Xp2l.3-Xp22.1,44the position ofZFX/ZFYappears to satisfy the condition for the chro-mosomal location of the Turner gene(s). Al-though Page et a128 have reported that a femalewith 46,X,t(Y;22) missing ZFY (case 15) has noTurner stigmata, and Hecht et a145 have de-scribed a female with 46, X,t(X;Y)(p1 .2;ql 1)and no apparent Turner stigmata, the findingsbased on the patients lacking Turner stigmatawould not provide compelling evidence againstZFX/ZFY being the Turner gene. Since, toour knowledge, there has been no report docu-menting a patient with characteristic Turnerstigmata in the presence of two copies of ZFX/ZFY, the possity that ZFX/ZFY could be acandidate Tirner gene has not been excludedformally. By contrast, RPS4X/RPS4Y isunlikely to be the Turner gene. The position ofRPS4X at Xq1343 is inappropriate for theTurner gene. Furthermore, Just et al46 havereported that the transcription rate of RPS4X

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is normal or increased in Turner patients with46,X,Xp- and 46,X,i(Xq). Although detailedphenotypes are not described in the report,46

this would provide strong evidence againstRPS4X/RPS4Y being the Turner gene.

In summary, although genotype-phenotypeanalysis of the putative Turner gene(s) on Ypis still not conclusive, we propose that theTurner gene(s) is located in the Y specificregion from lAlA to 2B. In addition, assess-

ment of ZFX/ZFY and RPS4X/RPS4Y in thecontext of the Turner gene(s) suggests thatZFX/ZFY rather than RPS4X/RPS4Y couldbe a candidate for the Turner gene.

We would like to thank Professor Peter Good-fellow for his critical comments, and Dr AlisonColley for the clinical information and bloodcollection.

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