1. Introduction

ASM

Advances in Sexual Medicine

2164-5191

Scientific Research Publishing

10.4236/asm.2020.102002

ASM-99042

Articles

Medicine&Healthcare

A Rare Case of 83-Year-Old Transgender Female: Can Thyroid Hormone Deficiency Be Involved in Transgenderism and Gender Dysphoria?

Andrey

Frolov

¹Lauren

Polcaro

¹Craig

Lawson

¹Yun

Tan

¹John

R. Martin III

¹^*

Center for Anatomical Science and Education, Department of Surgery, School of Medicine, Saint Louis University, Saint Louis, Missouri, USA

23032020

1002234012, February 202021, March 2020 24, March 2020

2014

This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

In the current report, we describe an 83-year-old biological male who self- identified as a female by legally changing his first and middle names to female ones and whose death certificate states his sex as a female. The medical history of this individual indicated complete penectomy without further specification. Postmortem physical examination revealed an absence of penis with a large scrotum, transposed urethral orifice, and small testes. The histological analysis of the testes identified abnormal epithelium in the seminiferous tubules that lacked germ and Sertoli cells as well as the interstitium without Leydig cells present. The exome sequencing of the individual’s DNA using the Next Generation Sequencing (NGS) Illumina platform revealed no genetic variants associated with either penile or urethral cancer that could have explained the complete penectomy, but pointed toward a potentially impaired production of T3 and T4 thyroid hormones which could account for the observed testicular malformation. Overall, the data obtained raise an important question as to whether the thyroid hormone axis could be an important part of the hormonal architecture supporting male sexual behavior.

Transgenderism Gender Dysphoria Next Generation Sequencing Thyroid Peroxidase Cilia

1. Introduction

Transgender (TG) is a broad term, which describes an individual whose gender self-identification is different from the assigned sex at birth. When the latter becomes overwhelming and causes a significant psychological impact, the term gender dysphoria (GD) is used thereby presenting itself as an extreme case of TGism. The individuals with GD often seek a medical intervention, surgical or therapeutic, to correct the existing discordance between their gender self-identification and physical appearance [1].

As of 2016, approximately 1.4 million adults identify as TG in the United States [2]. The TG biological underlining is not well understood. Genetically, it appears that interplay between sex steroid receptor polymorphisms, particularly those of androgen and estrogen, which are associated with TG [3]. Yet the RYR3 variant was identified in the Han Chinese population with GD [4] and CYP17 single nucleotide polymorphism was linked to female-to-male TGism [5] whereas a common SRD5A2 polymorphism has been shown recently to be benign in TGism (ClinicalTrials.gov Identifier: NCT00435513). Chromosomal aberrations, such as in Klinefelter syndrome (47, XXY), could also be responsible for GD in some individuals since a 1.13% frequency of patients with Klinefelter syndrome was found in GD population [6].

Metabolically, GD has been linked to androgen insensitivity in biological males. Individuals with complete androgen insensitivity syndrome (CAIS) have a 46, XY karyotype, bilateral testes, and female external genitalia [7]. These individuals tend to be psychosocially female and oriented toward men [8]. Individuals with partial androgen insensitivity syndrome (PAIS) also have a 46, XY karyotype, but may have penoscrotal hypospadias, micropenis, bifid scrotum, and undescended testes [9].

Most recently, a large cohort association study involving 380 transgender females (TFs) and 344 control male subjects revealed an over-representation in TFs of several allele combinations including androgen receptor (AR) that were proposed to feminize male individuals thereby leading to TGism [10].

Therefore, the main objective of this study was to provide in-depth examination of the current TF body to gain additional important insights into the respective biological underlinings through a systematic approach including gross anatomical dissection, histological analysis, and genetic screen using NGS technology.

2. Methods2.1. Human Cadaveric Body Procurement

An 83-year-old TF cadaver was received through Saint Louis University (SLU) School of Medicine Gift of Body Program from an individual who had given his written informed consent. The body was embalmed through the right femoral artery with a mixture of water and a solution (2:1) containing 33.3% glycerin, 28.8% phenol, 4.6% formaldehyde, and 33.3% methanol.

2.2. Anatomical Dissection

The cadaveric body was dissected according to [11].

2.3. Histological Analysis

Testicular tissue was procured from the embalmed body. Tissue fixation, paraffin embedding, sectioning, and staining with hematoxylin & eosin were performed by Research Microscopy and Histology Core, Department of Pathology, Saint Louis University (SLU) School of Medicine according to the standardized procedures. Images were captured on Olympus 41BX-EPI microscope equipped with the 10× UPlan FL N, 20× LUCPlan FL, and 40× UPlan FL N objectives. The data acquisition and image analysis were performed by using CellSens Standard software.

2.4. Bone Densitometry

Bone density of the lumbar spine and left femoral neck of the embalmed body was measured in triplicates using certified Hologic QDR-4500 X-ray Bone Densitometer in the dual energy X-ray absorptiometry (DEXA) mode following the manufacturer’s protocol. The respective average T-score values were used throughout the text.

2.5. Genetic Analysis

The Next Generation Sequencing (NGS) and bioinformatics analysis were performed as previously described [12] [13] with the following modifications. DNA extracted from the tibia specimen procured from the embalmed TF body was sequenced to 30× depth of coverage (~4.5 Gb) on the Illumina HiSeq 2500 NGS platform in the 2 × 100 base read format. DNA extraction was performed by Paleo-DNA Laboratory (Lakehead University, Canada) and exome sequencing was conducted by Omega Bioservices (Norcross, GA). The cumulative exome coverage for > 25× depth of coverage was 93% indicating that almost all of the exome was accessible for probing. The variant call and annotation were performed by Genome Technology Access Center (GTAC, Washington University in St. Louis) using SnpSift varType and ANNOVAR. The resultant data were converted into the Microsoft Excel format and pathologic (deleterious) variants were identified through the five consecutive filtering steps described in [12] [13]. Functional annotation of the remaining variants was performed using UniProtKB Protein, Google Scholar, and PubMed database searches.

3. Results3.1. Anatomical Characterization

A body of an 83-year-old individual with the male sex assigned at birth was received through the Gift of Body Program at the Center for Anatomical Science and Education (CASE) of the SLU School of Medicine, USA. The records indicated that this individual self-identified as a female by legally changing his first and middle names to female ones later in his life and his death certificate listed his sex as a female. It was also self-reported by the body donor that in the adulthood he/she underwent a complete penectomy without further specification. The body was hairless with an exception of a sparse hair on the scalp (Figure 1(A)), had a large scrotum with no penis observed (Figure 1(B)), and the urethral orifice was identified posterior to the scrotum (Figure 1(C)). A scrotum dissection revealed that the ductus deferens, epididymis, and testes were all intact (Figure 2(A)). However, the latter were much smaller than normal with the volume ~3.3 cm³ (Figure 2(A)) versus ~7.5 cm³ for the age matched normal individuals [14]. Dissection of the pelvic cavity revealed normal male anatomy with the seminal vesicles and ductus deferens located posterior to the bladder (Figure 2(B)). The prostate was also intact, positioned inferiorly to the bladder (Figure 2(C)).

3.2. Histological Analysis

Histological analysis of testicular tissue revealed abnormal seminiferous tubule epithelium. As compared to the age matched control body, the epithelium was devoid of germ and Sertoli cells and Leydig cells were not observed in the interstitium (Figure 2(D)).

3.3. Bone Densitometry

Because the results of histological analysis were indicative of testicular malformation and, consequently, hormone deficiency with the latter being commonly linked to osteoporosis, the bone mineral density in the cadaveric body was assessed by dual-energy X-ray absorptiometry (DEXA) scanning of the lumbar spine and left femoral neck yielding the respective T-score values of −3.1 and −3.4. These values are characteristic of osteoporosis (http://www.bones.nih.gov) and may serve as an indirect measure of the hormone deficiency in the examined body.

3.4. Genetic Analysis

The assessment of this individual karyotype was impossible due to incompatibility of the available methodologies with the biological material procured from the embalmed cadaveric body. However, the measured individual’s height of 1.73 m was significantly lower as compared to that of 1.83 m average for the Klinefelter syndrome patients [15], which along with the absence of other phenotypic characteristics such as gynecomastia [15] (Figure 1(A)) allows, although incomplete, exclusion of the respective 47, XXY chromosomal aberration from further consideration.

The putative genetic underlining of the present TF case was addressed by sequencing the entire coding regions of DNA (exome) extracted from the embalmed cadaveric tissue using NGS Illumina platform as described previously [12] [13]. The rare genetic variants (minor allele frequency, MAF ≤ 0.01) linked to deleterious (pathological) amino acid substitutions in the mutant proteins were identified through the five sequential, stringent filtering steps described in [12] [13]. In total, the genetic screen yielded 144 deleterious (pathological) variants of 137 genes with none of them associated with either penile or urethral cancer, or the genes known to regulate the androgen hormone axis (Table S1).

However, six genetic variants, TPO, BBS12, DNAH9, ITF81, OFD1, and TAPT1 could be linked directly to our case (Table 1) due to their involvement in the regulation of a thyroid hormone production (TPO) and male sex organ development through the control of cilia function (BBS12, DNAH9, ITF81, OFD1, and TAPT1) [12].

4. Discussion

The condition presented in the current report could be described as TGism with its progression to GD. The latter conclusion was based on the absence of genetic variants known to be associated with either penile or urethral cancer which puts forward an elective surgery as a primary cause for the reported complete penectomy.

Table 1 Selected deleterious (pathological) variants associated with the current TF

Gene	Protein Function	Variant
TPO	Thyroid peroxidase. Iodination and coupling of the hormonogenic tyrosines in thyroglobulin to yield the thyroid hormones T3 and T4.	c.1181_1182insCGGC: p.D394fs
BBS12	Bardet-Biedl syndrome 12 protein. Component of the chaperonin-containing T-complex (TRiC), a molecular chaperone complex that assists the folding of proteins upon ATP hydrolysis. As part of the TRiC complex may play a role in the assembly of BBSome, a complex involved in ciliogenesis regulating transports vesicles to the cilia.	c.T116C:p.I39T
DNAH9	Dynein heavy chain 9, axonemal. Force generating protein of respiratory cilia. Produces force towards the minus ends of microtubules.	c.T9534G:p.F3178L
ITF81	Intraflagellar transport protein 81 homolog. Component of the intraflagellar transport (IFT) complex B: together with IFT74, forms a tubulin-binding module that specifically mediates transport of tubulin within the cilium.	c.174delA:p.58fs
OFD1	Oral-facial-digital syndrome 1 protein. Component of the centrioles controlling mother and daughter centrioles length. Involved in the biogenesis of the cilium, a centriole-associated function.	c.702delA:p.A234fs
TAPT1	Transmembrane anterior posterior transformation protein 1 homolog. Plays a role in primary cilia formation.	c.A704C:p.H235P

It is hypothesized herein that one of the important underlinings of the above condition could be linked to the impaired T3 and T4 thyroid hormone production which could negatively affect a cross-talk between the thyroid and androgen hormone axes [16] [17] thereby potentially leading to anatomical and physiological alterations similar to those in PAIS [9]. This hypothesis is based on: 1) a presence of TPO deleterious (pathological) variant that control the T3 and T4 production and the absence of the variants that regulate the androgen hormone axis (Table 1); 2) the observed testicular malformation at both the anatomical and histological levels (Figure 2); and 3) the T-score values derived for the lumbar spine (−3.1) and femoral neck (−3.4) being comparable to those of patients with PAIS [18] while being much worse than those of older male subjects with low testosterone levels, respectively −0.48 and −1.56 [19]. Importantly, the T3 and T4 thyroid deficiency has been recently reported in a patient with GD and normal, 46, XX, female karyotype [20]. With this regard, the data presented in the current report raise a very important question is to whether the thyroid hormone deficiency could be viewed as one of the important biological underlinings of TGism and GD. It should also be noted, that prenatal maternal thyroid deficiency has been previously linked to impacting sexuality [21] [22].

The detected deleterious (pathological) BBS12, DNAH9, ITF81, OFD1, and TAPT1 variants known to negatively affect cilia development and function could serve as a prerequisite for other male sex organ malformations ambiguously present in the current case, such as hypospadias (Figure 1(B)) [12] and complete penoscrotal transposition [23]. Intriguingly, in the model organisms, cilium has also been shown to be a major regulator of male sexual behavior such as mate searching and selection [24] [25] [26].

5. Conclusion

The results reported in the current study provide unique information for the hypothesis that thyroid hormone deficiency could be one of the important biological underlinings of TGism and GD that merits its further evaluation in a clinical setting.

Acknowledgements

We gratefully acknowledge Dr. Paul Cliften (GTAC, Washington University in St. Louis, St. Louis, MO, USA) for his invaluable assistance with the bioinformatics analysis as well as Caroline Murphy and Barbara Nagel (SLU) for their skillful help with the histology slides preparation. Dr. Maria Teresa Tersigni-Tarrant is acknowledged for her assistance with the anatomical dissection.

Limitations

The deleterious (pathologic) genetic variants were identified by the exome sequencing of a single proband. The high scientific value of a single proband approach to unique human cases has been recently demonstrated [27].

Authors’ Contributions

AF designed the study, coordinated genetics data collection and bioinformatics analysis, analyzed the data, wrote and revised the manuscript. LP participated in designing the study, collected and analyzed the anatomical and bone densitometry data, and performed functional annotation of genetic variants. CL analyzed the histological data. YT assisted with the anatomical data collection and analysis. JRM designed and supervised the study, analyzed the data, wrote and revised the manuscript.

Funding

This study was supported by the Center for Anatomical Science and Education, SLU School of Medicine.

Disclosure

These data were presented in part at the Annual Experimental Biology Meeting (FASEB J. (2019), 33: Suppl. 1, Abstract lb109).

Conflicts of Interest

The authors declare no conflicts of interest regarding the publication of this paper.

Cite this paper

Frolov, A., Polcaro, L., Lawson, C., Tan, Y. and Martin III, J.R. (2020) A Rare Case of 83-Year-Old Transgender Female: Can Thyroid Hormone Deficiency Be Involved in Transgenderism and Gender Dysphoria? Advances in Sexual Medicine, 10, 23-40. https://doi.org/10.4236/asm.2020.102002

Supplementary Materials

The file contains Table S1 (Complete list of deleterious (pathologic) genetic variants associated with the current TF).

Table S1 Complete list of deleterious (pathologic) genetic variants associated with the current TF

Gene	Protein Function
ABCA13	ATP-binding cassette sub-family A member 13. ATPase activity, coupled to transmembrane movement of substances. Lipid transport. Neutrophil degranulation.
ABCC1	Multidrug resistance-associated protein 1. Mediates export of organic anions and drugs from the cytoplasm. Hydrolyzes ATP with low efficiency.
ABL1	Tyrosine-protein kinase ABL1. Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion, receptor endocytosis, autophagy, DNA damage response and apoptosis.
ADAMTS9	A disintegrin and metalloproteinase with thrombospondin motifs 9. Cleaves the large aggregating proteoglycans, aggrecan and versican. Has a protease-independent function in promoting the transport from the endoplasmic reticulum to the Golgi apparatus of a variety of secretory cargos.
ADIG	Adipogenin. Brown fat cell differentiation. Positive regulation of fat cell differentiation. Spermatogenesis.
AGBL1	Cytosolic carboxypeptidase 4. Metallocarboxypeptidase that mediates deglutamylation of target proteins. Catalyzes the deglutamylation of polyglutamate side chains generated by post-translational polyglutamylation in proteins such as tubulins.
ANKRD20A1	Ankyrin repeat domain-containing protein 20A1.
ANKRD20A3	Ankyrin repeat domain-containing protein 20A3.
ARHGAP21	Rho GTPase-activating protein 21. Functions as a GTPase-activating protein (GAP) for RHOA and CDC42. Downstream partner of ARF1 which may control Golgi apparatus structure and function
ARSD	Arylsulfatase D. Glycosphingolipid metabolism.
BAGE2	B melanoma antigen 2. Candidate gene encoding tumor antigens.
BAGE3	B melanoma antigen 3. Candidate gene encoding tumor antigens.
BBS12	Bardet-Biedl syndrome 12 protein. Component of the chaperonin-containing T-complex (TRiC), a molecular chaperone complex that assists the folding of proteins upon ATP hydrolysis. As part of the TRiC complex may play a role in the assembly of BBSome, a complex involved in ciliogenesis regulating transports vesicles to the cilia (PubMed: 20080638).
BCLAF1	Bcl-2-associated transcription factor 1. Death-promoting transcriptional repressor.
BZRAP1	BZRAP1 protein. Benzodiazepine receptor binding.
C4A	Complement C4-A. Non-enzymatic component of C3 and C5 convertases and thus essential for the propagation of the classical complement pathway. Covalently binds to immunoglobulins and immune complexes and enhances the solubilization of immune aggregates and the clearance of IC through CR1 on erythrocytes.

C4B	Complement C4-B.
C4B_2	Complement C4-B2.
C9	Complement component C9. Constituent of the membrane attack complex (MAC) that plays a key role in the innate and adaptive immune response by forming pores in the plasma membrane of target cells (PubMed:9634479, PubMed:9212048, PubMed: 26841934).
CACNA2D3	Voltage-dependent calcium channel subunit alpha-2/delta-3. The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel. Acts as a regulatory subunit for P/Q-type calcium channel (CACNA1A),
CBLC	E3 ubiquitin-protein ligase CBL-C. Acts as an E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome. Functionally coupled with the E2 ubiquitin-protein ligases UB2D1, UB2D2 and UB2D3. Regulator of EGFR mediated signal transduction; upon EGF activation, ubiquitinates EGFR. Isoform 1, but not isoform 2, inhibits EGF stimulated MAPK1 activation.
CCDC144NL CCDC144NL CCDC144NL	Putative coiled-coil domain-containing protein 144 N-terminal-like. Could be the product of a pseudogene. Shares high sequence similarity with the N-terminus of the CCDC144 family.
CCSER2	Serine-rich coiled-coil domain-containing protein 2. Microtubule-binding protein which might play a role in microtubule bundling.
CD200R1L	Cell surface glycoprotein CD200 receptor 2. Regulates neuroinflammatory response.
CDC27	Cell division cycle protein 27 homolog. Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle.
CEPT1	Choline/ethanolaminephosphotransferase 1. Catalyzes both phosphatidylcholine and phosphatidylethanolamine biosynthesis from CDP-choline and CDP-ethanolamine, respectively. Involved in protein-dependent process of phospholipid transport to distribute phosphatidyl choline to the lumenal surface.
CGN	Cingulin. Probably plays a role in the formation and regulation of the tight junction (TJ) paracellular permeability barrier.
CNGA2	Cyclic nucleotide-gated olfactory channel. Odorant signal transduction is probably mediated by a G-protein coupled cascade using cAMP as second messenger.
CNTRL	Centriolin. Involved in cell cycle progression and cytokinesis. During the late steps of cytokinesis, anchors exocyst and SNARE complexes at the midbody, thereby allowing secretory vesicle-mediated abscission.
COL11A1	Collagen alpha-1(XI) chain. May play an important role in fibrillogenesis by controlling lateral growth of collagen II fibrils.
CYP1A2	Cytochrome P450 1A2. Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics.

DNAH9	Dynein heavy chain 9, axonemal. Force generating protein of respiratory cilia. Produces force towards the minus ends of microtubules. Dynein has ATPase activity; the force-producing power stroke is thought to occur on release of ADP.
DPH6	Diphthine--ammonia ligase. Amidase that catalyzes the last step of diphthamide biosynthesis using ammonium and ATP.
EFTUD1	Elongation factor-like GTPase 1. Involved in the biogenesis of the 60S ribosomal subunit and translational activation of ribosomes.
FAM104A	Protein FAM104A. Highest level of expression is in sperm.
FAM63A	Protein FAM63A, aka MINDY1. Ubiquitin carboxyl-terminal hydrolase MINDY-1. Hydrolase that can specifically remove “Lys-48”-linked conjugated ubiquitin from proteins. May play a regulatory role at the level of protein turnover.
FAM81B	Protein FAM81B.
FOXD4L6	Forkhead box protein D4-like 6. Transcription factor. Anatomical structure morphogenesis. Cell differentiation.
FPR2	Formyl peptide receptor 2. High affinity receptor for N-formyl-methionyl peptides (FMLP), which are powerful neutrophil chemotactic factors (PubMed: 12218158, PubMed: 10477558, PubMed: 19387439). Receptor for the chemokine-like protein FAM19A5, mediating FAM19A5-stimulated macrophage chemotaxis and the inhibitory effect on TNFSF11/RANKL-induced osteoclast differentiation (PubMed: 29138422).
GAGE13	G antigen 13. This gene belongs to a multigene family expressed in a large variety of tumors whereas in normal tissues, expression is restricted to germ cells.
GAGE2E	G antigen 2E.
GAGE8	G antigen 8.
GGT1 GGT1 GGT1	Glutathione hydrolase 1 proenzyme. Initiates extracellular glutathione (GSH) breakdown, provides cells with a local cysteine supply and contributes to maintain intracellular GSH level. It is part of the cell antioxidant defense mechanism.
GRHL3	Grainyhead-like protein 3 homolog. Transcription factor playing important roles in primary neurulation and in the differentiation of stratified epithelia of both ectodermal and endodermal origin.
GTF3C1	General transcription factor 3C polypeptide 1. Required for RNA polymerase III-mediated transcription.
GYG1	Glycogenin-1. Self-glucosylates, via an inter-subunit mechanism, to form an oligosaccharide primer that serves as substrate for glycogen synthase.
HLA-A	MHC class I HLA-A protein. Involved in the presentation of foreign antigens to the immune system.
IFT81	Intraflagellar transport protein 81 homolog. Component of the intraflagellar transport (IFT) complex B: together with IFT74, forms a tubulin-binding module that specifically mediates transport of tubulin within the cilium. Required for ciliogenesis (PubMed: 27666822, PubMed: 23990561). Required for proper regulation of SHH signaling (PubMed: 27666822).
JPH4	Junctophilin-4. Junctophilins contribute to the formation of junctional membrane complexes (JMCs) which link the plasma membrane with the endoplasmic or sarcoplasmic reticulum in excitable cells. Provides a structural foundation for functional cross-talk between the cell surface and intracellular calcium release channels.

KCNG4	Potassium voltage-gated channel subfamily G member 4. Potassium channel subunit that does not form functional channels by itself. Can form functional heterotetrameric channels with KCNB1. Regulates ion transmembrane transport.
KIAA1549L	UPF0606 protein KIAA1549L.
KIR2DL1 KIR2DL1	Killer cell immunoglobulin-like receptor 2DL1. Receptor on natural killer (NK) cells for some HLA-C alleles such as w4 and w6. Inhibits the activity of NK cells thus preventing cell lysis.
KIR2DL3	Killer cell immunoglobulin-like receptor 2DL3. Receptor on natural killer (NK) cells for HLA-C alleles (HLA-Cw1, HLA-Cw3 and HLA-Cw7). Inhibits the activity of NK cells thus preventing cell lysis.
KIR2DS4 KIR2DS4 KIR2DS4	Killer cell immunoglobulin-like receptor 2DS4. Receptor on natural killer (NK) cells for HLA-C alleles. Does not inhibit the activity of NK cells.
KRTAP10-6	Keratin-associated protein 10-6. In the hair cortex, hair keratin intermediate filaments are embedded in an interfilamentous matrix, consisting of hair keratin-associated proteins (KRTAP), which are essential for the formation of a rigid and resistant hair shaft through their extensive disulfide bond cross-linking with abundant cysteine residues of hair keratins.
LCN12	Epididymal-specific lipocalin-12. Binds all-trans retinoic acid and may act as a retinoid carrier protein within the epididymis. May play a role in male fertility (By similarity).
LDLRAD4	Low-density lipoprotein receptor class A domain-containing protein 4. Functions as a negative regulator of TGF-beta signaling and thereby probably plays a role in cell proliferation, differentiation, apoptosis, motility, extracellular matrix production and immunosuppression.
LIPC	Hepatic triacylglycerol lipase. Hepatic lipase has the capacity to catalyze hydrolysis of phospholipids, mono-, di-, and triglycerides, and acyl-CoA thioesters. It is an important enzyme in HDL metabolism.
LPIN3	Phosphatidate phosphatase LPIN3. Regulates fatty acid metabolism. Magnesium-dependent phosphatidate phosphatase enzyme which catalyzes the conversion of phosphatidic acid to diacylglycerol during triglyceride, phosphatidylcholine and phosphatidylethanolamine biosynthesis (By similarity).
MAML3	Mastermind-like protein 3. Acts as a transcriptional coactivator for NOTCH proteins. Has been shown to amplify NOTCH-induced transcription of HES1.
MRGPRX1	Mas-related G-protein coupled receptor member X1. Orphan receptor activated by neuropeptides terminating in Arg-Phe or Arg-Phe-amideMay regulate the function of nociceptive neurons by modulation of pain perception.
MST1L MST1L	Putative macrophage stimulating 1-like protein.
MUC4 MUC4	Mucin-4. May play a role in tumor progression. Ability to promote tumor growth may be mainly due to repression of apoptosis as opposed to proliferation. Has anti-adhesive properties.
MYO1H	Unconventional myosin-Ih. Represents an unconventional myosin.
NBPF10	Neuroblastoma breakpoint family member 10.. RNA binding.
NBPF12 NBPF12	Neuroblastoma breakpoint family member 12. RNA binding.
NBPF20	Neuroblastoma breakpoint family member 20. RNA binding.

NCF1	Neutrophil cytosol factor 1. NCF2, NCF1, and a membrane bound cytochrome b558 are required for activation of the latent NADPH oxidase (necessary for superoxide production).
NEBL	Nebulette. Binds to actin and plays an important role in the assembly of the Z-disk. May functionally link sarcomeric actin to the desmin intermediate filaments in the heart muscle sarcomeres (PubMed: 27733623).
NFATC1	Isoform 2 might play a role in the assembly of focal adhesion (PubMed: 15004028).
NPTN	Neuroplastin. Probable homophilic and heterophilic cell adhesion molecule involved in long term potentiation at hippocampal excitatory synapses through activation of p38MAPK. May also regulate neurite outgrowth by activating the FGFR1 signaling pathway. May play a role in synaptic plasticity (By similarity).
NUDT22	Uridine diphosphate glucose pyrophosphatase. Hydrolyzes UDP-glucose to glucose 1-phosphate and UMP and UDP-galactose to galactose 1-phosphate and UMP. Preferred substrate is UDP-glucose.
NUP153	Nuclear pore complex protein Nup153. Component of the nuclear pore complex (NPC), a complex required for the trafficking across the nuclear envelope.
NUP58	Nucleoporin p58/p45. Component of the nuclear pore complex, a complex required for the trafficking across the nuclear membrane.
OFD1	Oral-facial-digital syndrome 1 protein. Component of the centrioles controlling mother and daughter centrioles length. Recruits to the centriole IFT88 and centriole distal appendage-specific proteins including CEP164. Involved in the biogenesis of the cilium, a centriole-associated function. Plays an important role in development by regulating Wnt signaling and the specification of the left-right axis.
OPALIN	Transmembrane protein.
OR11H1	Olfactory receptor 11H1
OR6N2	Olfactory receptor 6N2
PCDHA8	Protocadherin alpha-8. Potential calcium-dependent cell-adhesion protein. May be involved in the establishment and maintenance of specific neuronal connections in the brain.
PCK2	Phosphoenolpyruvate carboxykinase [GTP], mitochondrial. Catalyzes the conversion of oxaloacetate (OAA) to phosphoenolpyruvate (PEP), the rate-limiting step in the metabolic pathway that produces glucose from lactate and other precursors derived from the citric acid cycle.
PDCL3	Phosducin-like protein 3. Acts as a chaperone for the angiogenic VEGF receptor KDR/VEGFR2, controlling its abundance and inhibiting its ubiquitination and degradation. Modulates the activation of caspases during apoptosis.
PEX6	Peroxisome assembly factor 2. Involved in peroxisome biosynthesis.
PGM2L1	Glucose 1,6-bisphosphate synthase.
PLA2G4C	Cytosolic phospholipase A2 gamma. Has a preference for arachidonic acid at the sn-2 position of phosphatidylcholine as compared with palmitic acid.
PLCD4	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-4. Hydrolyzes the phosphatidylinositol 4,5-bisphosphate (PIP2) to generate 2 second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3).

PLXNB3	Plexin-B3. Receptor for SEMA5A that plays a role in axon guidance, invasive growth and cell migration.
POTEC	POTE ankyrin domain family member C. Highest expression level is in testis.
PPIAL4G	Peptidyl-prolyl cis-trans isomerase A-like 4G. PPIases accelerate the folding of proteins.
PRAMEF18	PRAME family member 18. Negative apoptosis regulation. Negative regulation of cell differentiation.
PRAMEF22	PRAME family member 22. Negative apoptosis regulation. Negative regulation of cell differentiation.
PRF1	Perforin-1. Plays a key role in secretory granule-dependent cell death, and in defense against virus-infected or neoplastic cells. Plays an important role in killing other cells that are recognized as non-self by the immune system, e.g. in transplant rejection or some forms of autoimmune disease.
PSMA8	Proteasome subunit alpha-type 8. Component of the spermatoproteasome, a form of the proteasome specifically found in testis that promotes degradation of histones, thereby participating actively to the exchange of histones during spermatogenesis.
RBMX	RNA-binding motif protein, X chromosome. RNA-binding protein that plays several role in the regulation of pre- and post-transcriptional processes.
RBMXL1	RNA binding motif protein, X-linked-like-1. RNA-binding protein which may be involved in pre-mRNA splicing.
RGS11	Regulator of G-protein signaling 11. Inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits thereby driving them into their inactive GDP-bound form.
RIT2	GTP-binding protein Rit2. Binds and exchanges GTP and GDP. Binds and modulates the activation of POU4F1 as gene expression regulator.
RLN3	Relaxin-3. May play a role in neuropeptide signaling processes. Ligand for LGR7, relaxin-3 receptor-1 (GPCR135) and relaxin-3 receptor-2 (GPCR142).
SAMD10	Sterile alpha motif domain-containing protein 10.
SCN9A	Sodium channel protein type 9 subunit alpha. Plays a role in pain mechanisms, especially in the development of inflammatory pain.
SETX	Probable helicase senataxin. Probable RNA/DNA helicase involved in diverse aspects of RNA metabolism and genomic integrity. Plays a role in neurite outgrowth in hippocampal cells through FGF8-activated signaling pathways. Inhibits retinoic acid-induced apoptosis (PubMed: 21576111).
SFXN1	Sideroflexin-1. Might be involved in the transport of a component required for iron utilization into or out of the mitochondria.
SLC22A13	Solute carrier family 22 member 13. Nicotinate transmembrane transporter activity.
SLC23A2	Solute carrier family 23 member 2. L-ascorbate:sodium symporter activity.
SLC25A5 SLC25A5	ADP/ATP translocase 2. Catalyzes the exchange of cytoplasmic ADP with mitochondrial ATP across the mitochondrial inner membrane.

SLC9B1	Sodium/hydrogen exchanger 9B1. Sperm-specific Na+/H+ exchanger involved in intracellular pH regulation of spermatozoa. Involved in sperm motility and fertility.
SLFN13	Schlafen family member 13. Endoribonuclease that cleaves tRNAs and rRNAs (PubMed:29563550).
SORD	Sorbitol dehydrogenase. Oxidoreductase activity. Zinc ion binding.
SPATA31A1	Spermatogenesis-associated protein 31A1. May play a role in spermatogenesis.
SPATA31C1	Putative spermatogenesis-associated protein 31C1. May play a role in spermatogenesis.
SPATA31C2	Putative spermatogenesis-associated protein 31C2. May play a role in spermatogenesis.
SPATS1	Spermatogenesis-associated serine-rich protein 1. Highest expression level is in testis.
SUGCT	Succinate--hydroxymethylglutarate CoA-transferase. Catalyzes the succinyl-CoA-dependent conversion of glutarate to glutaryl-CoA.
SYNE3	Nesprin-3. As a component of the LINC (LInker of Nucleoskeleton and Cytoskeleton) complex involved in the connection between the nuclear lamina and the cytoskeleton.
TAPT1	Transmembrane anterior posterior transformation protein 1 homolog. Plays a role in primary cilia formation (PubMed: 26365339).
TEX29	Testis-expressed protein 29. Highest expression level is in right testis.
THBS2	Thrombospondin-2. Adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions. Ligand for CD36 mediating antiangiogenic properties.
TLE2	Transducin-like enhancer protein 2. Regulation of transcription.
TM4SF19	Transmembrane 4 L6 family member 19. Highest expression level is in ectocervix.
TNXB	Tenascin-X. Appears to mediate interactions between cells and the extracellular matrix. Substrate-adhesion molecule that appears to inhibit cell migration. Accelerates collagen fibril formation. May play a role in supporting the growth of epithelial tumors.
TPO	Thyroid peroxidase. Iodination and coupling of the hormonogenic tyrosines in thyroglobulin to yield the thyroid hormones T3 and T4.
TUBGCP6	Gamma-tubulin complex component 6. Gamma-tubulin complex is necessary for microtubule nucleation at the centrosome.
TYRO3	Tyrosine-protein kinase receptor TYRO3. Regulates many physiological processes including cell survival, migration and differentiation.
WHSC1	Histone-lysine N-methyltransferase NSD2. Histone methyltransferase with histone H3 “Lys-27” (H3K27me) methyltransferase activity. Isoform 2 may act as a transcription regulator that binds DNA and suppresses IL5 transcription through HDAC recruitment.
ZNF563	Transcription regulation.
ZNF585B	Transcription regulation.

ZNF717 ZNF717 ZNF717 ZNF717 ZNF717	Transcription regulation.
ZNF846	Transcription regulation.
ZXDA ZXDA	Cooperates with CIITA to promote transcription of MHC class I and MHC class II genes.

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