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Original Studies |
Division of Endocrinology (S.S.S., Y.-S.Z., L.-Q.C., M.D.K., J.I.-M.), Diabetes and Metabolism, Department of Medicine, Cornell University Medical College, New York, New York 10021; and University of National Pedro Henriquez Urena (C.H., M.D.-R.), Santo Domingo, Dominican Republic
Address all correspondence and requests for reprints to: Julianne Imperato-McGinley, M.D., Cornell University Medical College, 1300 York Avenue, Room F-260, New York, New York 10021.
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Abstract |
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Genetic analysis of the LHR revealed a homozygous missense mutation at
exon 11 of the LHR gene. Guanine was replaced by adenine
(GAA
AAA), resulting in a substitution
of lysine for glutamic acid (glu) at amino acid position 354 of the
receptor. This mutation is located in the extracellular domain adjacent
to the first transmembrane helix of the LHR. Glutamic acid at position
354 of the LHR has been highly conserved throughout evolution.
Functional analysis of the LHR mutation, using an in
vitro mutagenesis-transfection assay, demonstrated complete
loss of function, indicated by the lack of cAMP production after human
CG stimulation in transfected human embryonic kidney 293 cells.
Screening of family members demonstrated heterozygosity for the
mutation, indicating autosomal recessive inheritance. Delineation of
the specific genetic defect in this family confirms recent reports that
a single mutation in the LHR gene causes male pseudohermaphroditism in
46XY subjects and primary amenorrhea in 46XX subjects. More
importantly, it also defines a new region of the LHR molecule that is
critical for biologic activity.
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Introduction |
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TopAbstractIntroductionCase reportsMaterials and MethodsResultsDiscussionReferences |
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- reduced product of T,
acts locally to stimulate development of male external genitalia and
prostate (12, 13). An abnormality in any of these processes, at a
critical period in utero, will result in abnormal sexual
differentiation. In normal male sexual differentiation, placental human CG (hCG) binds to the LH receptor (LHR) of the Leydig cell, causing Leydig cell differentiation and resultant T production during the critical 8th–14th weeks of gestation (14, 15, 16). Failure of the LHR of Leydig cells to respond to hCG leads to a decrease or absence of T secretion and resultant male pseudohermaphrodism in 46XY individuals (17, 18, 19, 20, 21, 22, 23, 24, 25).
In contrast, normal ovarian differentiation and function are not required for normal female phenotypic development. However, during puberty and adulthood, LH stimulates ovarian thecal cells, via the LHR, to produce androgens, which are converted to estrogen by ovarian granulosa cells under the stimulation of FSH (26, 27). The crucial role of LHR seems to be in the mid-to-late follicular phase of the menstrual cycle, where it is acted upon by LH to promote follicular maturation and the development of a dominant follicle (28). The LH surge is mandatory for ovulation. In the luteal phase, LH stimulates corpus luteum formation and progesterone production.
In the present study, we report three sisters who were found to be homozygous for a unique LHR mutation. Two of the sisters (XY, XX) presented with primary amenorrhea. The 46XY sisters had external female genitalia with slight clitoromegaly, inguinal testes, and no breast development. The 46XX sister had a normal female phenotype and good breast development.
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Case reports |
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TopAbstractIntroductionCase reportsMaterials and MethodsResultsDiscussionReferences |
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, subject
V-3). She was first evaluated at age 17. The subject is the offspring
of a consanguineous marriage; her parents are second cousins (Fig. 1, subjects IV-3 and IV-27). She was the product of a normal spontaneous
delivery, with no maternal history of gestational drug exposure. She is
the eldest of eight siblings. Her mother was 14 yr old at the time of
delivery. The subject had an uneventful childhood and experienced
continued growth at age 15.
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The subject underwent gonadectomy at age 24, and the inguinal testes were removed. Histology confirmed the absence of Leydig cells. Sertoli cells, spermatogonia, and primary spermatocytes were seen. Atrophic vasa deferentia and epididymides were present. Bone age was 13 yr, by the method of Greulich and Pyle (29).
Case 2. The fourth-born 46XY sibling was a phenotypic and
psychosexual female (Fig. 1
, subject V-7), who presented at age 10 with
bilateral inguinal masses and slight clitoral enlargement. This sibling
was the product of normal spontaneous delivery, without a history of
drug exposure during pregnancy. She had female external genitalia with
mild clitoromegaly, in addition to gonads that were bilaterally
palpable in the inguinal regions. She died at age 20 of a malignant
Schwannoma before genetic analysis of the LHR gene.
Case 3. The fifth-born sibling was 46XX (Fig. 1, subject V-8).
She was 16 yr old at the time of evaluation and was a phenotypic and
psychosexual female, who presented with primary amenorrhea. This
subject was the product of normal spontaneous delivery, with no history
of gestational drug exposure. She underwent thelarche at 9–10 yr of
age and adrenarche at age 11–12. Her mother and maternal aunts
experienced menarche at age 11. Her height was 151 cm., and her wt was
116 lbs (52.6 kg). Physical examination was notable for Tanner stage 5
breast development and Tanner stage 4 pubic hair. She had normal female
external genitalia and decreased axillary hair. Transabdominal
sonography revealed bilateral ovaries of normal size with evidence of
stimulation, as suggested by the cystic appearance of the left ovary. A
normal sized uterus was present.
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Materials and Methods |
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TopAbstractIntroductionCase reportsMaterials and MethodsResultsDiscussionReferences |
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hCG stimulation was initially performed on the 46XY sisters in
1989 using 1500 IU hCG, administered im three times per week for six
doses. A second hCG stimulation test was performed on the proband in
1996 with 2000 U hCG (Pregnyl, Organon, Inc., West Orange, NJ) given im
every other day for six doses. Plasma T, DHT, and
4-androstenedione (4) levels were
measured 24 h after the final dose of hCG.
Plasma hormones
Plasma T, DHT, and 4 were measured at baseline and after hCG
stimulation, by RIA, after separation by paper chromatography, as
previously described (30). Dehydroepiandrosterone sulfate was measured
by RIA. Plasma estradiol concentrations were determined pre- and post
hCG, by double antibody RIA (Diagnostic Product Corp., Los Angeles, CA)
(31). Plasma LH and FSH concentrations were measured in duplicate by
immunofluorometric assay, a highly sensitive, time-resolved
immunofluorescence assay (Delfia Pharmacia-Wallac, Turku, Finland)
(31).
Provera challenge
The 46XX sister was given 5 mg medroxyprogesterone acetate (Provera, Upjohn, Kalamazoo, MI) orally on days 1–12 of the calendar month.
PCR amplification and DNA sequencing
Blood was drawn into EDTA-containing tubes, and genomic DNA from white blood cells was isolated using a Qiagen genomic DNA isolation kit (Qiagen, Chatsworth, CA). The concentrations of DNA were determined by ultraviolet absorbance.
PCR amplification and labeling of exons 1–11 of the LHR gene were
carried out using primers and conditions previously described (32),
with minor modifications (available upon request). Five sets of inner
primers were used for exon 11. The reaction mixture contained 0.12 µg
or 0.36 µg genomic DNA, 200 µmol/L of each of four
deoxyribonucleoside triphosphates, 1 µmol/L of each primer, 10 mmol/L
Tris-HCl (pH 8.3), 50 mmol/L KCl, 1.5 mmol/L MgCl2, 0.1% Triton X-100,
and 2.5 U thermostable DNA polymerase; 10 µCi
[-32P]deoxy-ATP was added for the hot PCR. The samples
were denatured at 94 C for 2 min and then sequentially denatured at 94
C for 30 sec, annealed at the temperature and duration previously
described (32) with minor modifications, and extended at 72 C for 30
sec for a total of 35 cycles. A final extension cycle consisted of 72 C
for 10 min. Sequencing of PCR-amplified products was performed with
32P-end-labeled primer using an fmol DNA sequencing kit
(Promega, Madison, WI).
Single-strand DNA conformational polymorphism (SSCP) analysis
SSCP analysis was performed as previously described (32a), with some modifications. Exon DNA was amplified and radiolabeled as described above. One microliter of the PCR product was added to 9 µL formamide denaturing dye (98% formamide, 20 mmol/L EDTA, 10 mmol/L NaOH, and 0.05% each of xylene cyanol and bromophenol blue) and then denatured at 100 C for 6 min and immediately cooled on ice. Three microliters of this solution were loaded onto a 0.5 x Hydrolink MDE gel (J. T. Baker Inc., Phillipsburg, NJ), containing 10% glycerol, and electrophoresed at 350 volts at room temperature overnight in 0.6 x TBE buffer (54 mmol/L Tris-borate, pH 8.3, and 2.4 mmol/L EDTA). An aliquot of hot PCR sample was diluted in sucrose loading buffer (60% sucrose, 50 mmol/L EDTA, and 0.05% each of xylene cyanol and bromophenol blue) and loaded in an adjacent lane, without denaturation, to determine the position of migration of the double-stranded DNA fragment. After electrophoresis, the gel was dried and exposed to Kodak X-OMAT film (Eastman Kodak, Rochester, NY) at room temperature.
Denaturing gradient gel electrophoresis (DGGE)
DGGE analysis of exon 11 of the LHR gene was performed using GC-clamp primers, as previously described (33). Briefly, fragments of exon 11 of the LHR gene were amplified by PCR using GC-clamp primers with thermal cycle conditions, as described above. Amplified exon DNA was denatured in 95 C for 10 min and reannealed by cooling down slowly to room temperature, and it was then electrophoresed in an 8% denaturing gradient polyacrylamide (19:1 acrylamide:bisacrylamide) gel in 0.5 x TBE buffer. The 100% denaturant was 7 mol/L urea plus formamide (60:40, by volume). Intermediate denaturants were prepared by diluting 100% denaturant with 8% acrylamide in 0.5 x TBE. Gradients were prepared bottom-up by gravity flow in a gradient maker. A Bio-Rad Miniprotein apparatus, with 1.5-mm spacers, was used for all of the experiments. The results were visualized by ethidium bromide staining.
In vitro mutagenesis and transfection studies
An expression vector (pCMX-LHR), containing the entire coding region of the human LHR gene, was kindly provided by Dr. A. J. W. Hsueh (Stanford University, Stanford, CA). Using in vitro mutagenesis (QuickChange Site-Directed Mutagenesis Kit from Stratagene, La Jolla, CA), a new subclone was constructed with a substitution of guanine by adenine at position 1060 of the human LHR gene. The sequences of all constructs were confirmed by DNA sequencing.
Human embryonic kidney 293 cells (ATCC, Rockville, MD) were grown in DMEM, supplemented with 10% FBS, 50 U/mL penicillin, and 50 µg/mL streptomycin. Cells (1.5 x 106) were plated in 60-mm dishes and transfected by the calcium phosphate precipitation method (ProFection, Promega, Madison, WI) with 10 µg expression vector, 2 µg RSV-ß-galactosidase plasmid, and pBluescript-SK plasmid, to a total of 15 µg DNA/dish, as previously described (34). Sixteen hours after transfection, the cells were washed, and they continued to grow in fresh medium for 48 h until treated with hCG at concentrations from 10–1000 ng/mL. Two hours after hCG treatment, the cells were harvested, and cellular extracts were prepared for ß-galactosidase activity measurements. The medium was collected for cAMP analysis, and the levels of cAMP were determined by RIA, according to the manufacturer’s instructions (Biotrak c-AMPm 125I assay system from Amersham, Arlington Heights, IL). The transfection efficiencies were monitored by measuring ß-galactosidase activity in the cellular extracts, and the cAMP levels were normalized with transfection efficiencies.
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Results |
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TopAbstractIntroductionCase reportsMaterials and MethodsResultsDiscussionReferences |
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Hormonal evaluation of the 46XY proband at baseline, and after hCG
stimulation, was performed at age 17 in 1989 and at age 24 in 1996,
with similar results (Table 1). In both
studies, plasma T and DHT levels were low, and they failed to increase
after hCG stimulation (Table 1). The baseline level of LH was markedly
elevated, with a normal-to-slightly elevated FSH level. Circulating
levels of precursor steroids did not rise after hCG stimulation (Table 1).
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).
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). During the second month of
medroxyprogesterone acetate administration, the 46XX sister experienced
vaginal bleeding.
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Genetic analysis
SSCP and/or DGGE was used to screen for a mutation of the LHR
gene. As shown in Fig. 2, DGGE analysis
of PCR-amplified products, located at the 5' end of exon 11, revealed
differences in the mobility of the bands between the normal control and
the affected subjects. Heterozygosity was demonstrated also in the
mother of the affected subjects. Similar changes were also observed by
SSCP analysis (data not shown).
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). A guanine (G) is substituted by
adenine (A) at position 1060 (the assignment starts at the translation
start codon) of the nucleic acid sequence, causing the replacement of
glutamic acid (Glu) by lysine (Lys) at amino acid position 354
(GAAAAA) of the human LHR. This mutation is
located in the extracellular domain adjacent to the transmembrane
domain of the human LHR (Fig. 4). No
other mutations were detected in the remainder of the coding regions of
the LHR gene in the affected proband (data not shown).
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and 2).
A phenotypically normal brother (V-5) was heterozygous for the same
mutation and has fathered two phenotypically normal children. Several
aunts and uncles of the proband were also found to be heterozygotes
(Fig. 1). In vitro mutagenesis-transfection analysis
The functional significance of this missense mutation was
evaluated using in vitro mutagenesis transfection analysis
in human embryonic kidney 293 cells, by measuring cAMP production, an
immediate downstream marker of LH action. As shown in Fig. 5, hCG treatment, at doses of 10–1000
ng/mL, produced a dose-dependent increase in cAMP concentration in the
medium of the wild-type LHR-transfected cells. At the highest hCG dose
used (1000 ng/mL), the level of cAMP in wild-type LHR transfected cells
was increased 12-fold, compared with vehicle control treatment. In
contrast, the same hCG treatment, in the mutant LHR-transfected cells,
failed to induce any cAMP production (indicating that the mutant LHR is
essentially functionally crippled).
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Discussion |
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TopAbstractIntroductionCase reportsMaterials and MethodsResultsDiscussionReferences |
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).
Thus, autosomal recessive inheritance was demonstrated by molecular
genetic analysis and by pedigree analysis, confirming
consanguinity.
The LHR gene mutation identified in this pedigree is a missense
mutation located on exon 11 at position 1060 of the nucleic acid
sequence, where an adenine (A) is substituted for a guanine (G),
resulting in a change of codon 354 (GAAAAA) of
the LHR, from Glu to Lys (G354L). This mutation is located in the
extracellular domain of the LHR, directly adjacent to the first
transmembrane domain. It is different from previously reported
homozygous LHR mutations (Fig. 4), which are located in transmembrane
domains 5 and 6 (35, 36, 37) and in the extracellular domain (38) of the
receptor, distant from the transmembrane domain.
Using in vitro mutagenesis-transfection analysis, the G354L
mutation of the human LHR caused complete loss of receptor function, as
indicated by the failure of cAMP production after hCG stimulation (Fig. 5). The substitution of an acidic amino acid, such as
Glu354, by a basic amino acid, Lys, could change the ionic
environment and the conformation of the receptor, resulting in receptor
inactivation (39). However, Thomas et al. (40) demonstrated
that deletion of a large portion of the extracellular domain adjacent
to the first transmembrane helix in the rat LHR did not alter the
specificity and affinity of LH binding. More specifically, Huang and
Puett (41) reported that this mutation of Glu to Lys in the rat LHR did
not alter the binding affinity of LH, but it completely eliminated the
hCG-stimulated cAMP production in transfected COS-7 cells.
Glu354 and the surrounding amino acids are a highly
conserved region (see Fig. 6) in the
human, rat, and porcine LHR (42, 43, 44); in the human, rat, monkey, and
ovine FSH receptor (FSHR) (45, 46, 47, 48); and in the human TSH receptor
(TSHR) (49), suggesting a significant role in receptor function. Taken
together, these results suggest that this highly conserved region
participates in transmembrane signaling and has a fundamental role in
signal transduction for all glycoprotein hormone receptors.
Interestingly, all reported mutations causing inactivation of the human
LHR are also located at highly conserved amino acids (35, 36, 37).
Alternatively, a mutation of LHR (50), reported in a nonconserved amino
acid, did not result in inactivation of the receptor.
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Defects in the LHR result in abnormal Leydig cell differentiation and function at a critical period of sexual differentiation in affected 46XY subjects. Inadequate T and DHT production results in the development of abnormal male external genitalia. The phenotypes of 46XY subjects with LHR defects are variable. At one end of the spectrum are phenotypic males with micropenis and primary hypogonadism (36, 50), and at the other end are males with either female external genitalia or severe ambiguity of the genitalia (36, 37, present report). These phenotypic variations can be explained, at least in part, by the various defects of the LHR gene. It has been demonstrated that different mutations of the gene can cause either complete (37, present report) or partial (38, 50) loss of LHR function.
One interesting finding in male pseudohermaphrodites with LHR defects is the presence of atrophic epididymides and vasa deferentia. The differentiation and development of the epididymides and vas deferentia is dependent on androgens, as evidenced by studies of individuals with complete androgen-insensitivity (56). The presence of Wolffian duct structures in 46XY subjects with LHR defects suggests that a low level of T production is sufficient for Wolffian duct differentiation at the critical period in utero. T could be concentrated by androgen-binding protein secreted by the Sertoli cells in the seminiferous tubules, to promote the Wolffian duct differentiation (22). An alternative hypothesis, based on rabbit embryonic studies, is that the initiation of androgen synthesis at the beginning of male sexual differentiation is independent of extragonadal hormone stimulation (15).
The 46XX sibling with the G354L mutation in the LHR, reported herein, presented with primary amenorrhea and normal pubertal breast development. Analyses of her clinical and hormonal data suggest that LH action is necessary for complete follicular development and for ovulation (26, 27, 28). These findings are in agreement with previous reports of 46XX subjects with LHR mutations and similar phenotypes (36, 37). Histological analysis of an ovarian biopsy in one subject demonstrated morphologically normal primordial, preantral, and antral follicles (despite absent preovulatory follicles, corpora lutea, and corpora albicans) (37). Studies of porcine ovaries indicate that LHR-like immunoactivity and LHR messenger RNA are present in later stages of follicular development but not in primordial or primary follicles (28, 57). These results support the concept that initial follicular growth is independent of LH stimulation.
It is of interest that mutations of the LHR gene can also cause male limited autosomal dominant precocious puberty (58). In affected male subjects, the mutant LHRs are constitutively activated in the absence of ligand binding, resulting in excessive production of gonadal steroids and precocious puberty. All reported mutations of the LHR gene in subjects with precocious puberty are located in transmembrane domains 5 and 6 (58), the same area involved in mutations causing inactivation of the LHR (35, 36, 37). However, in affected male subjects with an activated LHR gene mutation, 50% of the LHRs remain constitutively activated in the heterozygous state, leading to excessive production of gonadal sex steroids and precocious puberty.
In summary, a novel single-point mutation in the extracellular domain of the human LHR, adjacent to the first transmembrane domain, has been identified. This mutation causes complete inactivation of receptor function, resulting in male pseudohermaphroditism in the affected 46XY siblings and primary amenorrhea in the affected 46XX sibling of the same family.
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Acknowledgments |
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Footnotes |
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Received December 11, 1997.
Accepted February 24, 1998.
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References |
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TopAbstractIntroductionCase reportsMaterials and MethodsResultsDiscussionReferences |
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-reductase-2 gene mutation in the Dominican Republic. J Clin
Endocrinol Metab. 81:1730–1735.[Abstract]
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