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Sobre a diferenciação dos genitais humanos, sabemos que os mesmos tem originalmente
uma estruturação feminina, e são masculinizados apenas pela ação eficiente da DHT.
A testosterona é importante como matéria prima para a síntese do DHT, mas não
participa diretamente desse processo. Os tecidos genitais externos são
masculinizados pela ação direta de DHT no receptor de androgênios AR.
Genetic and hormonal control of male sexual differentiation.
Goldstein JL, Wilson JD.
Phenotypic sexual differentiation during embryogenesis is a complex process involving the action of at least 18 genes. These genes regulate gonadal differentiation, gonadal hormone formation, and in the male the cellular action of three necessary hormones, namely mullerian regression factor, testosterone, and dihydrotestosterone. Analysis of two of the mutations affecting sexual development is consistent with the thesis that the two androgens testosterone and dihydrotestosterone have separate and specific roles in virilization of the male urogenital tract, testosterone stimulating wolffian duct development and dihydrotestosterone mediating development of the urogenital sinus and external genitalia. In the disorder familial incomplete male pseudohermphroditism, type 2, deficient dihydrotestosterone formation is associated with a selective failure of virilization of the urogenital sinus and external genitalia, whereas the wolffian duct derivatives develop normally. On the other hand, in the testicular feminization syndrome there is a complete failure in the development of the male phenotype, indicating that the primary defect involves an abnormality in some biochemical step that is common to the action of both androgens. Evidence from studies in the submandibular gland of the mouse with testicular feminization suggest that the fundamental defect lies in the translocation and/or nuclear binding of the cytoplasmic androgen receptor. It remains to be proven whether these events in the postnatal, sexually dimorphic submandibular gland of the testicular feminization mouse reflect prenatal events occurring in the urogenital tissues during embryogenesis.
Dihydrotestosterone formation in cultured human fibroblasts. Comparison of cells from normal subjects and patients with familial incomplete male pseudohermaphroditism, Type 2.
The conversion of [1,2-3H]testosterone to [3H]dihydrotestosterone has been assessed in fibroblast monolayers grown from skin biopsies of foreskin, scrotum, and various nongential skins from 31 control men who varied in age from newborn to 25 years and three 46,XY subjects with hereditary male pseudohermaphroditism. Under the standardized conditions utilized in this study, the rate of dihydrotestosterone formation was greater in fibroblasts grown from genital skin (foreskin and scrotum) passages exhibit the same differentiation in dihydrotestosterone formation as the skin from which the fibroblasts were grown. Furthermore, 5alpha-reductase, the enzyme that converts testosterone to dihydrotestosterone, exhibits apparent similar substrate specificity in control foreskin fibroblasts and in the foreskin itself. Fibroblasts grown from the foreskin of two patients with familial incomplete male pseudohermaphroditism, type 2, an autosomal recessive disorder of phenotypic sexual differentiation, showed a marked deficiency in the capacity to form dihydrotestosterone. In contrast, fibroblasts grown from the scrotum of one 46,XY male with familial incomplete male pseudohermaphroditism, type 1, an apparent X-linked disorder of phenotypic sexual differentiation, formed dihydrotestosterone at a normal rate.
PMID: 1123350 [PubMed - indexed for MEDLINE]
Por outro lado, este primeiro artigo de Resko et al, mostra
que no cérebro, principalmente nas porções basais que são gênero diferenciadas e
importantes para a formação da identidade de gênero, a ação é da testosterona,
pela ação direta no AR e através de uma aromatização em estradiol.
Sendo assim, é muito importante a investigação detalhada da ação de T e DHT, e seus mecanismos, principalmente nos casos de PAIS e MAIS.
Selective activation of androgen receptors in the subcortical brain of male
cynomolgus macaques by physiological hormone levels and its relationship to
androgen-dependent aromatase activity.
J Clin Endocrinol Metab 1993 Jun
Abstract Aromatase activity (AA) is androgen dependent
and independent in subcortical regions of the nonhuman primate brain, but the
correlation of androgen receptor (AR) content with AA has not been demonstrated.
Thus, we castrated 10 adult male cynomolgus monkeys (Macaca fascicularis) and
divided them into 2 groups. One group (n = 6) received empty Silastic capsules,
whereas the second group (n = 4) received Silastic capsules filled with
testosterone (T). Animals were killed after 3 weeks. Microsomal AA and
cytosolic and nuclear AR were determined in specific brain regions
dissected from frozen sections. Sera from T-treated subjects contained
T, dihydrotestosterone, and LH levels that were not significantly different
from the precastration amounts (P < 0.05). Cytosolic AR concentrations
declined after T treatment in 12 of 20 brain areas studied (P < 0.05).
Nuclear AR levels, on the other hand, were significantly elevated after T
treatment (activated) only in the ventral medial nucleus (VMN) and infundibular
nucleus/median eminence (P < 0.05). AA distribution was significantly
different (P < 0.05) among 20 brain nuclei and subregions. The highest
activities were found in the bed nucleus of the stria terminalis, the medial
preoptic area, the medial and cortical amygdala, and the VMN. Lesser activities
were found in other brain regions. Physiological concentrations of T increased
AA only in the VMN and infundibular nucleus-median eminence (P < 0.05).
These data suggest that physiological levels of androgens are effective in
regulating AA only in those brain areas in which AR are activated.
A mencionada Torres & Jurberg Hypothesis, mencionada por MItaliano no debate de Wal Torres com Tom Mazur sobre identidade de gênero e intersexo, diz respeito a essa possibilidade.
Se o cérebro dos primatas, humanos inclusive, é masculinizado pela testeoterona, com e sem aromatização....e os genitais só pela ação direta de DHT.... casos de MAIS com hormonio seletividade entre a ação de ativação da transcrição de AR por T e por DHT não poderia explicar como pode haver a discordância de gênero entre o sistema neural e o sistema genital? Essa é a Torres & Jurberg Hypothesis, ou seja, a possibilidade de cérebro (e consequentemente identidade) e genitais caminharem de forma discordante e contraditória, o que explicaria, se não todos, pelo menos alguns casos de transexualismo.
Para essa hipótese poder ser válida, tem que ser comprovada a hormonio seletividade na ação de T e DHT em casos de MAIS.
Os próximos artigos mostram justamente isso....a hormonio seletividade num caso de PAIS... uma mais aumentada. Se pode existir para PAIS, deve poder existir para MAIS. E será que não poderia explicar a transexualidade, em alguns casos?
Certamente que sim.
Portanto, a nosso ver, a Torres & Jurberg Hypothesis ainda é apenas uma possibilidade, mas que dia a dia se mostra mais viável, com base nos resultados que vêm a público, em biologia molecular de esteróides.
The use of androgen receptor amino/carboxyl-terminal interaction assays to investigate androgen receptor gene mutations in subjects with varying degrees of androgen insensitivity.
Ghali SA, Gottlieb B, Lumbroso R, Beitel LK, Elhaji Y, Wu J, Pinsky L, Trifiro MA.
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, and Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
Five mutations in the ligand-binding domain (LBD) of the human androgen receptor (hAR) found in patients with varying degrees of androgen insensitivity syndrome (AIS) were investigated for their effects on receptor dynamics. These were Arg(871)Gly (mild), Ser(814)Asn (partial), Glu(772)Ala (partial), Val(866)Met (complete), and Arg(774)Cys (complete). Previous analysis showed that the mutant receptors exhibited near-normal kinetics, except Arg(774)Cys, which had severely reduced androgen binding, and Val(866)Met, which showed increased equilibrium dissociation constant (K(d)) and elevated dissociation rate (k) values. Ser(814)Asn exhibited ligand-selective k values, i.e. increased for dihydrotestosterone and mibolerone, but normal for methyltrenolene. Using mammalian two-hybrid assays, hAR amino/carboxyl (N/C)-terminal interactions of the mutant receptors were analyzed in the presence and absence of the hAR coactivator transcription intermediary factor 2 (TIF2). The mutations conferred decreased hAR N/C-terminal interaction, i.e. mild (approximately 1.5-fold), partial (2-fold), and complete (10-fold), that mirrored the degree of AIS. All mutant LBDs showed a 2- to 3-fold increase in N/C-terminal interactions when TIF2 was cotransfected, although of a magnitude still less than that of wild-type LBD with TIF2. The ligand-selective properties of the Ser(814)Asn mutant were also clearly reflected by the N/C-terminal interactions. Thus, measurement of N/C-terminal interactions may assist in the molecular analysis of mutant hARs associated with AIS.
PMID: 12727974 [PubMed - indexed for MEDLINE]
Discordant measures of androgen-binding
kinetics in two mutant androgen receptors causing mild or partial androgen
J Clin Endocrinol Metab 1999 Feb 84:805-10
Abstract We have characterized
two different mutations of the human androgen receptor (hAR) found
in two unrelated subjects with androgen insensitivity syndrome (AIS):
in one, the external genitalia were ambiguous (partial, PAIS); in the
other, they were male, but small (mild, MAIS). Single base
substitutions have been found in both individuals: E772A in the
PAIS subject, and R871G in the MAIS patient. In COS-1 cells transfected
with the E772A and R871G hARs, the apparent equilibrium dissociation
constants (Kd) for mibolerone (MB) and methyltrienolone are normal.
Nonetheless, the mutant hAR from the PAIS subject (E772A) has elevated
nonequilibrium dissociation rate constants (k(diss)) for both androgens.
In contrast, the MAIS subject's hAR (R871G) has k(diss) values that are
apparently normal for MB and methyltrienolone; in addition, the R871G
hAR's ability to bind MB resists thermal stress better than the hAR
from the PAIS subject. The E772A and R871G hARs, therefore, confer
the same pattern of discordant androgen-binding parameters in transfected
COS-1 cells as observed previously in the subjects' genital skin
fibroblasts. This proves their pathogenicity and correlates with
the relative severity of the clinical phenotype. In COS-1 cells
transfected with an androgen-responsive reporter gene, trans-activation
was 50% of normal in cells containing either mutant hAR. However, mutant
hAR-MB binding is unstable during prolonged incubation with MB, whereas
normal hAR-MB binding increases. Thus, normal equilibrium dissociation
constants alone, as determined by Scatchard analysis, may not be
indicative of normal hAR function. An increased k(diss) despite a
normal Kd for a given androgen suggests that it not only has increased
egress from a mutant ligand-binding pocket, but also increased access
to it. This hypothesis has certain implications in terms of the
three-dimensional model of the ligand-binding domain of the nuclear
The role of androgens in male gender role behavior.
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235-8857, USA. firstname.lastname@example.org
PMID: 10529900 [PubMed - indexed for MEDLINE]
Mais artigos sobre AIS, PAIS, MAIS, e detalhes da ação de AR
A novel point mutation in the hormone binding domain of the
androgen receptor associated with partial and minimal androgen insensitivity
J Pediatr Endocrinol Metab 2003 Feb 16:149-54
Abstract Mutations in the coding sequence of the androgen receptor
(AR) gene result in a wide range of androgen insensitivity syndromes (AIS).
We report an extended family in which at least five male individuals in
different generations suffer from partial AIS. The index patient presented
at birth with ambiguous genitalia; the karyotype was 46,XY and subsequent
sex assignment male. Elevated stimulated testosterone (T) and normal
baseline gonadotropins were found. Family history revealed four additional
adult males affected with various abnormalities of their external genitalia.
Molecular analysis of the coding sequence of the AR gene revealed in all a
novel point mutation in exon 6, changing threonine to isoleucine at codon
position 800 in the hormone-binding domain. We conclude that phenotypic
variations in mild AR defects are striking and can remain undetected even
until late in life.
Spinobulbar muscular atrophy: polyglutamine-expanded androgen receptor is proteolytically resistant in vitro and processed abnormally in transfected cells.
Abdullah A, Trifiro MA, Panet-Raymond V, Alvarado C, de Tourreil S, Frankel D, Schipper HM, Pinsky L.
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Cote Sainte Catherine Road, Montreal, Quebec H3T 1E2, Canada.
The neuronotoxicity of genes with expanded CAG repeats is most likely mediated by their respective polyglutamine (Gln)-expanded gene products. Gln- expanded portions of these products may be sufficient, or necessary, for pathogenesis. We tested whether a Gln-expanded human androgen receptor (AR) is structurally altered, so that it allows for the proteolytic generation of a potentially pathogenic portion that may be resistant to further degradation. We found, in vitro , that a Gln-expanded AR is more proteolytically resistant than normal, and that it yields a distinct set of Gln-expanded fragments even after extended proteolysis in the presence of 2 M urea. Furthermore, COS cells transfected with CAG-expanded AR cDNA generate an aberrant, nuclear-associated 75 kDa derivative containing the Gln-expanded tract. They are also twice as likely to die by 24 h apoptotically than those transfected with normal AR cDNA. Our data support the notion that an unconventional derivative of the Gln- expanded AR is a component of the proximate motor neuronopathic agent in spinobulbar muscular atrophy. They also focus attention on two ways in which neuronotoxic derivatives may originate from various Gln-expanded proteins: (i) generation of an unusual derivative that is pathogenic de novo ; and (ii) the toxic accumulation of a normal derivative because of an inability to dispose of it.
A G577R mutation in the human AR P box results in selective decreases in DNA binding and in partial androgen insensitivity syndrome.
Nguyen D, Steinberg SV, Rouault E, Chagnon S, Gottlieb B, Pinsky L, Trifiro M, Mader S.
Department of Biochemistry, Universite de Montreal, Montreal, Quebec H3C 3J7, Canada.
We have characterized a novel mutation of the human AR, G577R, associated with partial androgen insensitivity syndrome. G577 is the first amino acid of the P box, a region crucial for the selectivity of receptor/DNA interaction. Although the equivalent amino acid in the GR (also Gly) is not involved in DNA interaction, the residue at the same position in the ER (Glu) interacts with the two central base pairs in the PuGGTCA motif. Using a panel of 16 palindromic probes that differ in these base pairs (PuGNNCA) in gel shift experiments with either the AR DNA-binding domain or the full length receptor, we observed that the G577R mutation does not induce binding to probes that are not recognized by the wild-type AR. However, binding to the four PuGNACA elements recognized by the wild-type AR was affected to different degrees, resulting in an altered selectivity of DNA response element recognition. In particular, AR-G577R did not interact with PuGGACA palindromes. Modeling of the complex between mutant AR and PuGNACA motifs indicates that the destabilizing effect of the mutation is attributable to a steric clash between the C beta of Arg at position 1 of the P box and the methyl group of the second thymine residue in the TGTTCPy arm of the palindrome. In addition, the Arg side chain can interact with G or T at the next position (PuGCACA and PuGAACA elements, respectively). The presence of C is not favorable, however, because of incompatible charges, abrogating binding to the PuGGACA element. Transactivation of several natural or synthetic promoters containing PuGGACA motifs was drastically reduced by the G577R mutation. These data suggest that androgen target genes may be differentially affected by the G577R mutation, the first natural mutation characterized that alters the selectivity of the AR/DNA interaction. This type of mutation may thus contribute to the diversity of phenotypes associated with partial androgen insensitivity syndrome.
PMID: 11579211 [PubMed - indexed for MEDLINE]
A clinical syndrome of mild androgen insensitivity.
J Clin Endocrinol Metab 1984 Oct 59:672-8
Abstract We studied
four patients from three kindreds who had normal male body habitus and
external genitalia except for short penile length and gynecomastia.
Prostate size was small in all patients and spermatogenesis was decreased
markedly in one and absent in three. Testicular biopsies in two patients
revealed normal histology but evidence of spermatogenic arrest at the
spermatocyte stage. Circulating levels of testosterone and LH were
increased and the testosterone-dihydrotestosterone ratios were normal.
Plasma estradiol was elevated in three of the four patients. Serum FSH
levels were significantly elevated in only one patient. The response of
LH and FSH to LHRH stimulation was normal in the two patients who were
tested. Despite the normal male phenotype, the laboratory studies
suggested the diagnosis of androgen insensitivity. This was confirmed
in two patients by finding decreased dihydrotestosterone-binding capacity
in genital skin fibroblasts. Two of the patients had normal levels of
androgen receptor binding, suggesting that their defect represented a
mild form of androgen insensitivity with normal receptor activity. These
results demonstrated that mild forms of androgen insensitivity exist in
which the only obvious clinical manifestations may be the presence of
reduced penile length, gynecomastia, and/or infertility. The incidence of
androgen insensitivity among men with these subtle phenotypic abnormalities,
including infertility, remains to be determined.
A cell-specific and selective effect on
transactivation by the androgen receptor.
Exp Cell Res 1995 Apr 217:368-77
The androgen (AR) and glucocorticoid receptors (GR) are related
ligand-activated transcriptional regulators which bind the same
cis-acting element and are coexpressed in a variety of cell types.
Despite a shared DNA binding site, these receptors mediate diverse
cellular responses. To explain this paradox, the existence of cell-specific
factors that interact with, and modulate the function of, distinct receptors
has been proposed. Prostate epithelial cell growth is sensitive to androgens,
but is not affected by glucocorticoids, even though both AR and GR are
expressed in these cells. We have recently isolated a unique panel of
prostate epithelial cell lines from normal rats and have used these cell
lines to examine cell-specific steroid responses. In this study, we compared
the abilities of AR and GR to enhance transcription of several different
reporter genes regulated by simple (i.e., noncompsite) hormone response
elements (HREs) in prostate and nonprostate cell lines. The cell-specific
effect occurred independently of the AR hormone binding domain and could
be observed with a GAL4 fusion protein containing only the AR N-terminal
regulatory domain. Gel shift analyses showed that the relative DNA binding
affinity of AR for a probe containing a simple HRE was similar in prostate
and nonprostate cell extracts. Presently, the only factors known to mediate
steroid receptor-specific gene regulation are cJun and cFos, but there were
no cell-specific differences in the functional levels of these proteins
which could account for a preferential effect on AR-dependent transcription.
Taken together, these results suggest that cell-specific activities exist
which can preferentially modulate transcriptional transactivation by AR.
The relationship of androgen receptor levels to androgen responsiveness in the
Dunning R3327 rat prostate tumor sublines.
Barrack ER J Urol 1984 Oct 132:821-7
Abstract The objective of this
study was to determine whether androgen receptor levels in a
transplantable animal model of prostatic adenocarcinoma correlated
with androgen responsiveness of the tumor. This is the first
comparative study of androgen receptor levels in 3 subcellular
compartments (cytosol, nuclear salt-extractable and nuclear
salt-resistant fractions) of 4 Dunning R3327 rat prostatic adenocarcinoma
sublines that vary in their response to androgen ablation. Tumors were
harvested from intact adult male rats in order to best approximate the
human clinical setting in which receptor levels are quantitated prior
to androgen ablative therapy. Only the nuclear salt-resistant (nuclear
matrix) and total nuclear androgen receptor contents were significantly
different among all tumor sublines. The properties of the tumors studied
and their nuclear salt-resistant androgen receptor levels were as follows:
H tumor--well-differentiated, slow growing, androgen-dependent, 63 +/- 11
fmol./mg. DNA; HI tumor--well-differentiated, slow growing, androgen-
insensitive, 19 +/- 8 fmol./mg. DNA; G tumor--poorly-differentiated,
fast growing, androgen-sensitive, 195 +/- 42 fmol./mg. DNA; and AT-2
tumor--anaplastic, fast growing, androgen-insensitive, no detectable
receptors. There was no apparent quantitative relationship between
androgen receptor content and tumor growth rates, which varied
considerably irrespective of the androgen responsiveness of the tumor.
However, there was a qualitative relationship between nuclear
salt-resistant or total nuclear receptor content and androgen
responsiveness. Higher levels of receptor (H and G tumor sublines)
were associated with responsiveness to androgen ablation (cessation
or slowing of growth, respectively), whereas lower levels of receptor
(HI and AT-2 sublines) were associated with androgen insensitivity.
These observations, based on relatively homogeneous tumors, may have
important implications for human prostatic cancers which appear to be
composed of heterogeneous cell populations.
Um artigo muito importante, falando do efeito no feto da
gestação muito extressada das mães. Gunther Dörner, da Universidade Humboldt de
Berlin, já mostrava nos anos 70 que mães muito estressadas durante a gestação,
faziam com que seu sistema imunológico fragilizado pelo stress, inibisse a
produção de testosterona nos testículos dos fetos, podendo ocasionar uma falta
de testosterona para a adequada diferenciação do cérebro do feto. Este artigo
confirma o terrível efeito do stress durante a gestação.
Alterations induced by gestational stress in brain morphology and behaviour of the
offspring M. Weinstock Leon & Mina Deutsch Professor of
Progress in Neurobiology, 2001, 65:5:427 - 451
Manuscript received 25 January 2000 Accepted 22 August 2001;
Retrospective studies in humans
suggest that chronic maternal stress during pregnancy, associated with raised plasma
levels of CRH, ACTH and cortisol may increase the likelihood of preterm birth,
developmental delays and behavioural abnormalities in the children. In adulthood,
it may contribute to the significant association between the incidence of
schizophrenia, increased left or mixed handedness, reduction in cerebral
asymmetry and anomalies in brain morphology. Our studies and others have shown
that prenatal stress in rats can mimic these developmental and behavioural
alterations. These rats show a reduced propensity for social interaction,
increased anxiety in intimidating or novel situations and a reduction in cerebral
asymmetry and dopamine turnover, consistent with those in schizophrenic humans.
Prenatally-stressed (PS) rats also show behaviour consistent with depression,
including a phase-shift in their circadian rhythm for corticosterone, sleep
abnormalities, a hedonic deficit and greater acquisition of learned helplessness
under appropriate conditions. These behavioural abnormalities are associated
with impaired regulation of the hypothalamicpituitaryadrenal axis
response to stress and increased CRH activity. PS males may show demasculinisation
and feminisation of their sexual behaviour. The developmental and behavioural
abnormalities in PS offspring could occur through sensitisation of the foetal
brain by maternal stress hormones to the action of glucocorticoid and CRH and
to neurotransmitters affected by them. This may have long-lasting consequences
and could explain the precipitation of depressive symptoms or schizophrenia by
psychosocial stress in later life. The character of the behavioural abnormalities
probably depends on the timing of the maternal stress in relation to development
of the particular neuronal systems.
Artigos sobre genética e série de genes SRY no cromossomo Y
Mammalian sex reversal and intersexuality deciphering the sex-determination cascade
Daniel Vaiman and Eric Pailhoux The sex-determination
cascade constitutes a model of the exquisite mechanisms of gene regulation
that lead to the development of mammalian embryos. The discovery of
the sex-determining region of the Y... Trends in Genetics, 2000, 16:
cascade constitutes a model of the exquisite mechanisms of gene regulation that
lead to the development of mammalian embryos. The discovery of the sex-determining
region of the Y chromosome (SRY) in the early 1990s was the first crucial step
towards a general understanding of sex determination. Since then, several genes
that encode proteins with a role in this cascade, such as WT1, SF-1, SOX9, DAX-1
and WNT4, have been identified. Many of the interactions between these proteins
have still to be elucidated, while, no-doubt, others are still to be identified.
The study of mammalian intersexes forms a promising way towards the identification
of the still-missing genes and a comprehensive view of mammalian sex determination.
Intersexuality in the goat, studied for over a century, will, presumably, bring to
light new genes involved in the female sex-determination pathway.
Candidate genes in complete and partial XY sex reversal: Mutation analysis of
SRY, SRY-related genes and FTZ-F1 H.N. Lim, S.H. Freestone, D. Romero, C. Kwok, I.A. Hughes and
J.R. Hawkins Current address: SmithKline Beecham Pharmaceuticals, New
Frontiers Science Park, Harlow, Essex, U.K. Molecular and Cellular
Endocrinology, 1998, 140:1-2:51 - 58
The sexual phenotype is established in
three steps: (1) the sex chromosome constitution; (2) the differentiation of the
gonads; and (3) the response of the internal and external genitalia to the hormones
produced by the differentiated gonads. Errors that occur at any of these stages can
result in defective sexual differentiation. Therefore the investigation of patients
with abnormalities of testis development will help elucidate the mechanisms of sex
determination and gonadal differentiation. It was in this way that SRY, the
primary testis determining gene was identified. De novo mutations in SRY,
result in gonadal dysgenesis by disrupting the DNA-binding activity of the SRY
protein. However, only 20% of cases of gonadal dysgenesis, are explained by
mutations in SRY or its flanking sequences. Therefore, there are several
pieces to this puzzle yet to be discovered and it is hoped that mutation analysis
of other genes implicated in gonadal development and differentiation may shed some
light on aetiology of gonadal dysgenesis in the remaining 80% of cases.