*154230 SEX REVERSAL, AUTOSOMAL, 2; SRA2
Alternative
titles; symbols
TESTIS-DETERMINING FACTOR, AUTOSOMAL; TDFA
MALE-DETERMINING FACTOR, AUTOSOMAL
SEX REVERSAL, INCLUDED
ZFY-RELATED AUTOSOMAL SEQUENCES, INCLUDED
table OF
CONTENTS
"14
MEDLINE Citations"
"3 Protein Links"
"1 Nucleotide Link"
"1 Genome Link" "Gene
Map" "Nomenclature
Database"
Gene Map Locus: 9p24
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TEXT
Kasdan et al. (1973)
described a family in which a paternally
transmitted, non-Y, male-determining autosomal gene
was postulated as the only plausible explanation
for sex reversal. Over 40 men with a 46,XX
karyotype had been reported by 1972 (de
la Chapelle, 1972); see 278850.
The phenotype resembled that of the Klinefelter
syndrome. Translocation of Y-chromosome material to
an autosome could be excluded as the cause in at
least some cases. With the discovery of the SRY
('sex region on the Y') gene (480000)
and its equating to the TDF (testis-determining
factor) gene, it became possible to demonstrate
Y-chromosome material on one X chromosome in most
XX males.
Like Kasdan et al.
(1973) and Berger et al.
(1970), Skordis et al.
(1987) described XX true hermaphrodites and XX
males in the same family. In the report of
Skordis et al. (1987),
the propositus was a paternal uncle with 46,XX true
hermaphroditism. One of his brothers fathered a
46,XX daughter with true hermaphroditism; a second
brother fathered two 46,XX males. Both fathers had
normal male karyotypes and phenotypes. Skordis
et al. (1987) concluded that XX true
hermaphrodites and XX males represent alternative
manifestations of the same genetic defect and that
the abnormality occurs via paternal transmission of
an autosomal testis-determining factor. It was
pointed out by de la Chapelle
(1987) that in the several instances of
familial XX maleness and XX true hermaphroditism,
most affected persons are true hermaphrodites or XX
males with ambiguous genitalia, whereas XX males
without genital ambiguity are rare in such
families. No Y-chromosome DNA has been found in
familial cases. Typical autosomal dominant
inheritance of XX testicular differentiation occurs
in informative pedigrees. This led de
la Chapelle (1987) to the conclusion that an
autosomal dominant testis-determining factor, TDFA,
exists. TDFA shows somewhat variable expression in
XX persons, often causing genital ambiguity or true
hermaphroditism. TDFA has no phenotypic effect in
XY persons.
Kuhnle et al. (1993)
described a family with a 46,XX male and a 46,XX
true hermaphrodite sib. An offspring of a maternal
uncle had 46,XX true hermaphroditism. The maternal
as well as paternal transmission of the disorder
allows the possibility of either autosomal dominant
or X-chromosomal dominant inheritance. Since
molecular genetic analysis showed that both
hermaphrodites as well as the 46,XX male were
negative for Y-chromosomal sequences, testicular
determination seemed to be due to varying
expression of the same genetic defect, which
presumably was incompletely penetrant. A mutation
in an autosomal or X-chromosomal gene downstream
from SRY could have turned itself or another gene
into a TDF-like gene. In the case of the mutation
of an X-chromosomal gene, a different X
inactivation pattern could explain the different
phenotypes: random inactivation in XX true
hermaphrodites and nonrandom in XX males. They
pointed out that the 46,XX male could in fact have
been a true hermaphrodite with unambiguous male
external genitalia, since no surgical biopsy of
both gonads to exclude the presence of ovarian
parts was performed.
Affara et al. (1989)
identified a ZFY-related DNA sequence that mapped
to 9pter-9p22. Mapping was done by in situ
hybridization.
Pointing out that 4 cases of total sex reversal
in association with a de novo translocation
involving 9p have been described, Hoo
et al. (1989) suggested that 9p24 (the shortest
region of overlap) carries a gene important for
testis development. All 4 cases showed female
external genitalia and a uterus. Histologic studies
of the gonads in 2 cases showed immature testicular
tissue containing Sertoli cells but no germinal
cells. The gonads appeared to produce androgens in
normal amounts and responded to stimulation by HCG.
Since in most 9p deletion cases sex reversal is not
observed, Hoo et al.
(1989) postulated that there might be a
recessive gene on 9p24 that codes for a gene
product, probably an enzyme, important in the early
development of the testes. Lack of this gene
product causes delayed and incomplete testicular
formation. The 4 cases of sex reversal may have
occurred in individuals who carried a defective
gene on their normal chromosome 9 and concurrent
deletion of the healthy allele on the other
chromosome 9. Hoo et al.
(1989) pointed to camptomelia with sex reversal
(114290)
and autosomal recessive gonadal dysgenesis
(233420)
as disorders that also suggest the existence of
testis-forming genes on autosomes.
There are likely to be several genes in addition
to SRY involved in the early development of testes.
Bennett et al. (1993)
reported the case of a female infant with a de novo
deletion of distal 9p, sex reversal (the karyotype
was 46,XY), and an apparently intact SRY gene. They
reviewed 5 other reports of deletions of the distal
short arm of chromosome 9 in association with sex
reversal. Four of these involved a familial
translocation. The translocation was derived from
the mother in 2 cases and from the father in 2
cases, thus making imprinting unlikely.
See also H-Y antigen receptor (143150),
H-Y structural gene (143170),
XX male syndrome (278850),
H-Y regulator (306970),
gonadal dysgenesis, XY female type (233420,
306100).
Sex reversal mutations have been observed in the
goat (Hamerton et al.,
1969) and in the mouse (Cattanach
et al., 1971). The disorder is recessive in the
goat, but dominant in the mouse. In these cases the
autosomal gene apparently causes the indifferent
gonad of genetic females to differentiate partially
or completely into a testis. Selden
et al. (1978) studied an instructive family of
American cocker spaniels which suggested that
abnormality of sexual development (development of
testes or ovotestes) in animals with an XX
karyotype was caused by anomalous transmission of
H-Y genes. The observations suggested a common
basis for the XX male syndrome and for XX true
hermaphroditism.
Ion et al. (1998)
described a patient with failure of testicular
development and a chromosomal rearrangement
involving 9p24.1, in a region proximal to the SNF2
gene (600014).
They quoted Huret et al.
(1988) as finding that two-thirds of males with
a 9p deletion present with hypospadias or abnormal
external genitalia.
Flejter et al. (1998)
presented the cytogenetic and molecular analyses of
4 sex-reversed XY females, each with gonadal
dysgenesis and other variable malformations, and
with terminal deletions of distal chromosome 9p,
resulting from unbalanced autosomal translocations.
PCR amplification and DNA sequence analysis of SRY
revealed no mutations in the high-mobility-group
domain (i.e., HMG box) in any of the 4 patients.
Conventional and molecular cytogenetic analyses of
metaphase chromosomes from each patient suggested
that the smallest region of overlap (SRO) of
deletions involved a very small region of distal
band 9p24. Loss of heterozygosity (LOH) studies
using 17 highly polymorphic microsatellite markers,
as well as fluorescence in situ hybridization using
YAC clones corresponding to the most distal markers
on 9p, showed that the SRO lies distal to marker
D9S1779. Thus, the region occupied by the putative
sex-determining gene was narrowed to the very
terminal region of 9p. Previously Guioli
et al. (1998) performed a molecular analysis of
9p deletions associated with XY sex reversal,
thereby refining the localization of a
sex-determining gene to the tip of the chromosome.
Veitia et al. (1998)
reported studies of 2 patients with Swyer syndrome
(306100)
and 46,XY partial gonadal dysgenesis associated
with 9p deletions but without the rest of the
features of monosomy 9p syndrome (158170).
-
SEE ALSO
- de la Chapelle
(1987)
REFERENCES
- 1. Affara, N. A.;
Chambers, D.; O'Brien, J. :
- Habeebu, S. S. M.; Kalaitsidaki, M.;
Bishop, C. E. and Ferguson-Smith, M. A.:
Evidence for distinguishable transcripts of the
putative testis determining gene (ZFY) and
mapping of homologous cDNA sequences to
chromosomes X, Y and 9. Nucleic
Acids Res. 17: 2987-2999, 1989.
PubMed ID : 2498838
- 2. Bennett, C. P.;
Docherty, Z.; Robb, S. A.; Ramani, P.; Hawkins,
J. R.; Grant, D. :
- Deletion 9p and sex
reversal. J. Med. Genet. 30:
518-520, 1993.
PubMed ID : 8326498
- 3. Berger, R.;
Abonyi, D.; Nadot, A.; Vialatte, J.; Lejeune, J.
:
- Hermaphrodisme vrai et 'garcon XX'
dans une fratrie. Rev. Europ. Etud.
Clin. Biol. 15: 330-333, 1970.
- 4. Cattanach, B. M.;
Pollard, C. E.; Hawkes, S. G. :
- Sex-reversed mice: XX and XO
males. Cytogenetics 10:
318-337, 1971.
PubMed ID : 5156366
- 5. de la Chapelle,
A. :
- Evidence for the existence of an
autosomal testis determining gene, TDFA.
(Abstract) Cytogenet. Cell
Genet. 46: 605 only, 1987.
- 6. de la Chapelle,
A. :
- Nature and origin of males with XX
sex chromosomes. Am. J. Hum.
Genet. 24: 71-105, 1972.
PubMed ID : 4622299
- 7. de la Chapelle,
A. :
- The Y-chromosomal and autosomal
testis-determining genes.
Development 101 (suppl.): 33-38,
1987.
PubMed ID : 3503720
- 8. Flejter, W. L.;
Fergestad, J.; Gorski, J.; Varvill, T.;
Chandrasekharappa, S. :
- A gene involved in XY sex reversal
is located on chromosome 9, distal to marker
D9S1779. Am. J. Hum. Genet.
63: 794-802, 1998.
PubMed ID : 9718346
- 9. Guioli, S.;
Schmitt, K.; Critcher, R.; Bouzyk, M.; Spurr, N.
K.; Ogata, T.; Hoo, J. J.; Pinsky, L.; Gimelli,
G.; Pasztor, L.; Goodfellow, P. N. :
- Molecular analysis of 9p deletions
associated with XY sex reversal: refining the
localization of a sex-determining gene to the
tip of the chromosome. (Letter) Am.
J. Hum. Genet. 63: 905-908, 1998.
PubMed ID : 9718347
- 10. Hamerton, J.
L.; Dickson, J. M.; Pollard, C. E.; Grieves, S.
A.; Short, R. V. :
- Genetic intersexuality in
goats. J. Reprod. Fertil. 7
(suppl.): 25-51, 1969.
- 11. Hoo, J. J.;
Salafsky, I. S.; Lin, C. C.; Pinsky, L. :
- Possible location of a recessive
testis forming gene on 9p24. (Abstract)
Am. J. Hum. Genet. 45 (suppl.): A78
only, 1989.
- 12. Huret, J. L.;
Leonard, C.; Forestier, B.; Rethore, M. O.;
Lejeune, J. :
- Eleven new cases of del(9p) and
features from 80 cases. J. Med.
Genet. 25: 741-749, 1988.
PubMed ID : 3070043
- 13. Ion, R.; Telvi,
L.; Chaussain, J.-L.; Barbet, J. P.; Nunes, M.;
Safar, A.; Rethore, M.-O.; Fellous, M.;
McElreavey, K. :
- Failure of testicular development
associated with a rearrangement of 9p24.1
proximal to the SNF2 gene. Hum.
Genet. 102: 151-156, 1998.
PubMed ID : 9521582
- 14. Kasdan, R.;
Nankin, H. R.; Troen, P.; Wald, N.; Pan, S.;
Yanaihara, T. :
- Paternal transmission of maleness in
XX human beings. New Eng. J.
Med. 288: 539-545, 1973.
PubMed ID : 4685451
- 15. Kuhnle, U.;
Schwarz, H. P.; Lohrs, U.; Stengel-Ruthkowski,
S.; Cleve, H.; Braun, A. :
- Familial true hermaphroditism:
paternal and maternal transmission of true
hermaphroditism (46,XX) and XX maleness in the
absence of Y-chromosomal sequences.
Hum. Genet. 92: 571-576, 1993.
PubMed ID : 8262517
- 16. Selden, J. R.;
Wachtel, S. S.; Koo, G. C.; Haskins, M. E.;
Patterson, D. F. :
- Genetic basis of XX male syndrome
and XX true hermaphroditism: evidence in the
dog. Science 201: 644-646,
1978.
PubMed ID : 675252
- 17. Skordis, N. A.;
Stetka, D. G.; MacGillivray, M. H.; Greenfield,
S. P. :
- Familial 46,XX males coexisting with
familial 46,XX true hermaphrodites in same
pedigree. J. Pediat. 110:
244-248, 1987.
PubMed ID : 3806296
- 18. Veitia, R. A.;
Nunes, M.; Quintana-Murci, L.; Rappaport, R.;
Thibaud, E.; Jaubert, F.; Fellous, M.;
McElreavey, K.; Goncalves, J.; Silva, M.;
Rodrigues, J. C.; Caspurro, M.; Boieiro, F.;
Marques, R.; Lavinha, J. :
- Swyer syndrome and 46,XY partial
gonadal dysgenesis associated with 9p deletions
in the absence of monosomy-9p syndrome.
(Letter) Am. J. Hum. Genet.
63: 901-905, 1998.
PubMed ID : 9718353
CLINICAL
SYNOPSIS
View
Clinical Synopsis Entry
CONTRIBUTORS
Victor A. McKusick - updated : 9/16/1998
Victor A. McKusick - updated : 4/1/1998
CREATION DATE
Victor A. McKusick : 6/2/1986
EDIT HISTORY
alopez : 11/6/1998
alopez : 9/18/1998
terry : 9/16/1998
dholmes : 4/17/1998
alopez : 4/1/1998
terry : 3/23/1998
terry : 3/23/1998
mimadm : 11/6/1994
davew : 7/13/1994
terry : 5/12/1994
warfield : 4/21/1994
pfoster : 3/31/1994
carol : 2/24/1994
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