Search

Loss-of-function mutations in the immunoglobulin superfamily, member 1 (IGSF1) gene cause X-linked central hypothyroidism, and therefore its mutation affects mainly males. Central hypothyroidism in males is the hallmark of the disorder, however some patients additionally present with hypoprolactinemia, transient and partial growth hormone deficiency, early/normal timing of testicular enlargement but delayed testosterone rise in puberty, and adult macro-orchidism. Here, we report a boy with congenital central hypothyroidism caused by a novel variant in the IGSF1 gene. In our patient, early testicular enlargement but delayed testosterone rise with central hypothyroidism and hypoprolactinemia were the most important clues for diagnosis. In genetic analysis, we identified a novel, hemizygous nonsense c.3763 C>T (G1n1255Ter) variant in IGSF1 gene. To our knowledge, this is the first reported case of IGSF1 deficiency from Turkey.

Congenital hypothyroidism is the most frequent endocrine disorder in newborns, occurring in 1 per 3000-4000 newborns. In the Netherlands, the neonatal screening program is based primarily on heel prick thyroxine (T4). In contrast to thyroid-stimulating hormone-based programs, this approach allows for the detection of both primary and central congenital hypothyroidism. Over the past decade, the identification of families with isolated congenital central hypothyroidism enabled the identification of novel genetic causes of this condition, in addition to mutations in the TSHβ-subunit gene and thyrotropin-releasing hormone receptor gene reported earlier. In 2012, loss-of-function mutations in the immunoglobulin superfamily, member 1 (IGSF1) gene, were reported as a genetic cause of a syndrome including X-linked congenital central hypothyroidism and adult macroorchidism. IGSF1 encodes a hypothalamic plasma membrane glycoprotein. Mutations in IGSF1 represent the most prevalent genetic cause of isolated central hypothyroidism to date. In 2016, mutations in the transducin β-like 1X (TBL1X) gene were identified in patients with a combination of mild central hypothyroidism and sensorineural hearing loss. TBL1X is an essential subunit of the NCoR/SMRT corepressor complex and expressed in many tissues including the human hypothalamus and pituitary. In 2018, mutations in the insulin receptor substrate 4 (IRS4) gene were reported in cases of familial isolated central hypothyroidism. IRS4 encodes a hypothalamic protein that is part of the insulin and leptin signaling cascade. These recent developments will broaden our understanding of the role of the hypothalamus in hypothalamus-pituitary-thyroid axis regulation and will help to improve diagnosis and treatment of isolated central hypothyroidism.

In recent years, variants in immunoglobulin superfamily member 1 (IGSF1) have been associated with congenital hypopituitarism. Initially, IGSF1 variants were only reported in patients with central hypothyroidism (CeH) and macroorchidism. Later on, IGSF1 variants were also reported in patients with additional endocrinopathies, sometimes without macroorchidism. We studied IGSF1 as a new candidate gene for patients with combined CeH and growth hormone deficiency (GHD). We screened 80 male and 14 female Dutch patients with combined CeH and GHD for variants in the extracellular region of IGSF1, and we report detailed biomedical and clinical data of index cases and relatives. We identified three variants in our patient cohort, of which two were novel variants of unknown significance (p.L570I and c.1765+37C>A). In conclusion, we screened 94 patients with CeH and GHD and found variants in IGSF1 of which p.L570I could be of functional relevance. We provide detailed phenotypic data of two boys with the p.C947R variant and their large family. The remarkable phenotype of some of the relatives sheds new light on the phenotypic spectrum of IGSF1 variants.

Loss-of-function mutations of IGSF1 are an X-linked cause of central hypothyroidism (CeH) and hypoprolactinemia. A boy who is now 15.2 years old presented at the age of 7.69 years for evaluation of obesity. Previous thyroid function evaluation suggested CeH [FT4 0.6 ng/mL, thyroid-stimulating hormone (TSH) 2.2 mIU/L] but his physician took no action. At presentation he was clinically and biochemically euthyroid, prepubertal and obese. Serum prolactin (PRL) was undetectable. Biochemistry was normal except for mild hypercholesterolemia, total cholesterol 198 mg/dL. Subsequently FT4 and TSH levels fluctuated between 0.72-0.95 ng/dL (normal 0.8-2.0) and 1.94-5.77 mIU/L (normal 0.3-5.0), respectively. Sequencing of IGSF1 gene revealed a novel genetic change c.3805C>T in exon 19; substitution of amino acid Arginine at position 1269 with a premature «stop» codon resulting in an altered protein product. The patient additionally presented delayed adrenarche, low height velocity that resolved spontaneously and normal pubertal onset associated with increased FSH levels. At 14 years-of-age, while the patient was at Tanner stage 4, PRL levels became detectable, rising gradually to 2.3 ng/mL at last examination. Thyroxine replacement therapy resulted in decrease in total cholesterol 103 mg/dL. A high index of suspicion for the disorder is needed since several measurements of thyroid function may be required for CeH to be disclosed. The patient’s normal FT4 levels and normal intelligence would have resulted in a missed diagnosis if the serum PRL levels had not been measured. This case highlights the importance of measuring PRL in a boy with low normal FT4 and normal TSH levels.

Central congenital hypothyroidism (CH) is defined as thyroid hormone (TH) deficiency at birth due to insufficient stimulation by the pituitary of the thyroid gland. The incidence of central CH is currently estimated at around 1:13,000. Central CH may occur in isolation, but in the majority of cases (60%) it is part of combined pituitary hormone deficiencies (CPHD). In recent years several novel genetic causes of isolated central CH have been discovered (IGSF1,TBL1X,IRS4), and up to 90% of isolated central CH cases can be genetically explained. For CPHD the etiology usually remains unknown, although pituitary stalk interruption syndrome does seem to be the most common anatomic pituitary malformation associated with CPHD. Recent studies have shown that central CH is a more severe condition than previously thought, and that early detection and treatment leads to good neurodevelopmental outcome. However, in the neonatal period the clinical diagnosis is often missed despite hospital admission because of feeding problems, hypoglycemia and prolonged jaundice. This review provides an update on the etiology and prognosis of central CH, and a practical approach to diagnosis and management of this intriguing condition.

Thyroid cancer has been continuously increasing and extraordinarily prevalent worldwide. The genetic diagnosis has been widely used in fine needle aspiration. IGSF1, an immunoglobulin superfamily member 1, has been shown to be associated with the regulation of thyroid hormone. But the function of IGSF1 in thyroid cancer has not been explored yet. In this article, we will illuminate the correlation between IGSF1 expression and thyroid cancer. We analysed the level of IGSF1 expression in 55 pairs of tissue samples by real-time polymerase chain reaction (PCR) and The Cancer Genome Atlas (TCGA) data portal. After that, we transfected small interfering RNA to silence IGSF1 in thyroid cancer cell lines (KTC-1 and BCPAP) and confirmed the function of IGSF1 by performed colony formation, migration, invasion, cell counting kit-8, and apoptosis assays. IGSF1 was upregulated in thyroid cancer tissues compared with the adjacent normal tissues (t = 5.783, df = 54; P

Loss-of-function mutations in the X-linked immunoglobulin superfamily, member 1 (IGSF1) gene result in central hypothyroidism, often associated with macroorchidism. Testicular enlargement in these patients might be caused by increases in follicle-stimulating hormone (FSH) levels, as IGSF1 has been proposed to function as an inhibin B receptor or as an inhibitor of activin type I receptor (ALK4) activity in pituitary gonadotrope cells. If true, loss of IGSF1 should lead to reduced inhibin B action or disinhibition of activin signaling, thereby increasing FSH synthesis. Here, we show that FSH levels and sperm counts are normal in male Igsf1 knockout mice, although testis size is mildly increased. Sperm parameters are also normal in men with IGSF1 deficiency, although their FSH levels may trend higher and their testes are enlarged. Inhibin B retains the ability to suppress FSH synthesis in pituitaries of Igsf1-knockout mice and IGSF1 does not interact with ALK4 or alter activin A/ALK4 stimulation of FSHβ (Fshb/FSHB) subunit transcription or expression. In light of these results, it is unlikely that macroorchidism in IGSF1 deficiency derives from alterations in spermatogenesis or inhibin/activin regulation of FSH.

Objective To evaluate clinical characteristics of patients with central congenital hypothyroidism (CH), detected in the Dutch neonatal screening program. This included patients with isolated central CH but the majority have multiple pituitary hormone deficiencies (MPHD). Design Nationwide, cross-sectional study. Methods Data was collected on clinical characteristics, endocrine tests and neuroimaging of central CH patients, detected by the Dutch neonatal screening and born between 1 January 1995 and 1 January 2015. Height and pubertal status were assessed during a study visit. Isolated central CH patients without a confirmed genetic diagnosis were offered genetic (re-)testing. Results During the 20-year period 154 central CH patients were detected (incidence of permanent central CH 1:25 642). After excluding deceased (15), severe syndromic (7) and transient patients (6), 92 of 126 eligible patients were included (57 MPHD; 79% male). Sixty-one patients (50 MPHD) had been hospitalized before screening results were reported, but central CH was diagnosed on clinical grounds in only three of them (5%). MRI abnormalities consistent with pituitary stalk interruption syndrome were seen in 50 (93%) MPHD patients. Among isolated central CH patients, 27 (84%) had an IGSF1, TBL1X or IRS4 gene variant (53, 16 and 16%, respectively). Conclusion Many patients with central CH have neonatal health problems, especially MPHD patients. Despite hospital admission of two-thirds of patients, almost none were diagnosed clinically, but only after the notification of an abnormal screening result was received. This indicates that central CH, especially if isolated, is an easily missed clinical diagnosis.

Background: IGSF1 deficiency syndrome, also known as X-linked central hypothyroidism and testicular enlargement (CHTE) syndrome, is caused by mutations in the immunoglobulin superfamily, member 1 gene. Recently recognized as the most common genetic cause of isolated central hypothyroidism (CH), its cardinal features include CH and adult macroorchidism. We describe a boy with CH and epiphyseal dysplasia found to have a novel IGSF1 variant. Clinical case: A male with attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder, obsessive compulsive disorder and obesity was evaluated at age 9y for high total and LDL cholesterol and low T4 with normal TSH. He had short stature for family, high BMI, high sitting height ratio, and short arm span. Laboratory investigation revealed persistently mildly high total and LDL cholesterol, low T4, normal cortisol response to low-dose Cortrosyn stimulation, and normal IGF-1 and IGF-BP3. Bone age at 9y1m chronological age was 8y0m. Skeletal survey showed abnormal epiphyses of the femoral heads, knees, and humeral capitella suggesting primary epiphyseal dysplasia; he was referred to genetics. Growth improved after starting levothyroxine for CH. Multiple epiphyseal dysplasia gene panel (with reflex to clinical exome) did not find any variants known to be pathogenic for his condition. He was found to be a carrier of autosomal recessive Bartter syndrome. Heterozygous variants of unknown significance were found in RMRP, FGFR1, CDT1 and APOB. Whole exome sequencing showed hemizygosity for the p.Q743X (c.2227C>T) variant in IGSF1. Discussion: The p.Q743X IGSF1 variant has not been reported in the literature and is not present in population databases. It is predicted to cause loss of normal protein function and is considered pathogenic. CH is found in all males with IGSF1 deficiency syndrome. Macroorchidism, another defining feature, develops in adulthood; age of testicular growth onset is normal, but pubertal testosterone rise is delayed. Our patient remains prepubertal at age 11y. Other features sometimes present include hypoprolactinemia (which was found in this child) and transient partial GHD (not seen in this case). Overweight and the metabolic syndrome are common; this child’s cholesterol abnormalities may be due to weight and/or APOB variant found on genetic testing. ADHD has been seen in some patients with this syndrome; this child also has extensive psychiatric/behavioral problems, which have not been described. The skeletal findings in this case have not been previously noted in IGSF1 deficiency syndrome; whether this is a rare feature of IGSF1 deficiency syndrome or a separate entity is unclear. This case adds to the growing list of disease-causing variants in IGSF1. Endocrinologists should consider IGSF1 deficiency syndrome when diagnosing isolated CH in boys, as the characteristic macroorchidism is not present in childhood.

Context The X-linked immunoglobulin superfamily, member 1 (IGSF1), gene is highly expressed in the hypothalamus and in pituitary cells of the POU1F1 lineage. Human loss-of-function mutations in IGSF1 cause central hypothyroidism, hypoprolactinemia, and macroorchidism. Additionally, most affected adults exhibit higher than average IGF-1 levels and anecdotal reports describe acromegaloid features in older subjects. However, somatotrope function has not yet been formally evaluated in this condition. Objective We aimed to evaluate the role of IGSF1 in human and murine somatotrope function. Patients, Design, and Setting We evaluated 21 adult males harboring hemizygous IGSF1 loss-of-function mutations for features of GH excess, in an academic clinical setting. Main Outcome Measures We compared biochemical and tissue markers of GH excess in patients and controls, including 24-hour GH profile studies in 7 patients. Parallel studies were undertaken in male Igsf1-deficient mice and wild-type littermates. Results IGSF1-deficient adult male patients demonstrated acromegaloid facial features with increased head circumference as well as increased finger soft-tissue thickness. Median serum IGF-1 concentrations were elevated, and 24-hour GH profile studies confirmed 2- to 3-fold increased median basal, pulsatile, and total GH secretion. Male Igsf1-deficient mice also demonstrated features of GH excess with increased lean mass, organ size, and skeletal dimensions and elevated mean circulating IGF-1 and pituitary GH levels. Conclusions We demonstrate somatotrope neurosecretory hyperfunction in IGSF1-deficient humans and mice. These observations define a hitherto uncharacterized role for IGSF1 in somatotropes and indicate that patients with IGSF1 mutations should be evaluated for long-term consequences of increased GH exposure.

Pituitary development is coordinated by the timely interaction of several signaling pathways and transcription factors. The expression of lhx3 precedes that of transcription factors like tbx19, prop1, gata2 or sf1 and requires earlier expression of others like pitx1 and pitx2 and pathways like sonic hedgehog. The adult pituitary contains SOX2/SOX9 positive pituitary stem cells and progenitors leading to a differentiated pituitary, and in vitro differentiation of embryonic stem cells into mature pituitary cells was shown to recapitulate anterior pituitary development. Conditional inactivation of isl-1 in thyrotrophs induces central hypothyroidism, showing that this LIM domain factor is necessary for thyrotroph function. Large scale genomic techniques identified new pathogenic gene variants in constitutional hypopituitarism, an indirect evidence of their role in pituitary development or function: a variant of GPR161 was identified by whole exome sequencing in GH deficiency; a variant of ARNT2 was associated with constitutional panhypopituitarism, diabetes insipidus and microcephaly. Allelic variations of NFKB2 were associated with pituitary deficiency (mainly ACTH deficiency) and variable immune deficiency (VID), described as DAVID syndrome. IGSF1 alterations were identified in a complex X-linked phenotype with thyrotroph deficiency, macro-orchidism, delayed puberty, transient GH or ACTH deficiency, and low prolactin levels. The first variants of the potassium channel gene KCNQ1 were reported in families with GH deficiency, gingival fibromatosis and arrhythmia. Thanks to new genome wide techniques, more causative genes have been identified over the past 6 years than over the 2 decades following the first identification of the role of pou1f1 in human hypopituitarism. Demonstrating the role of these new genes will require an appropriate cell model that may derive from novel stem cell techniques. Such approaches will help better understand pituitary development and functions.

Background: IGSF1 abnormality causes diverse symptoms, including congenital central hypothyroidism (CCH), prolactin hyposecretion, testicular enlargement and delayed puberty. Case presentation: Here, we report a case of a male patient who visited our hospital with a chief complaint of abdominal pain and short stature, in whom we identified a novel IGSF1 mutation. He was closely examined because of chronic constipation since infancy, persistent abdominal pain at 14 years of age and marked short stature (−4.7 standard deviation [SD] for normal Japanese boys). He was diagnosed with CCH. Decreased prolactin (PRL) secretion was also observed. IGSF1 analysis revealed a novel mutation at the splicing donor site (c.2065+1G>A) in intron 11. In silico analysis predicted this mutation to be a non-functional splice donor site. After thyroid hormone replacement, his thyroid function, constipation and growth rate improved. Conclusions: This is the first report of a patient in whom constipation and short stature led to a diagnosis of CCH with a novel IGSF1 mutation.

Genetic defects in the immunoglobulin superfamily member 1(IGSF1) protein are the cause of congenital central hypothyroidism (C-CH). Here we report two Japanese siblings with C-CH due to a novel IGSF1 mutation. The youngest brother showed a failure to thrive, hypothermia, and neonatal icterus six days after birth. Further endocrine evaluations led to the diagnosis of C-CH. In addition, PRL deficiency was later detected. In contrast, the elder brother did not show symptoms of severe hypothyroidism during the neonatal period, but he had been followed up by doctors due to psychomotor developmental delays since the age of 1 yr. At the age of 3 yr, he had low thyroxine and PRL levels and was also diagnosed with C-CH. Because of the C-CH and PRL deficiency, an IGSF1 deficiency was suspected. Sequence analysis of the IGSF1 gene identified a novel hemizygous mutation of p.Trp1173GlyfsTer8 (NM_001170961.1:c.3517del) in both siblings. In conclusion, the phenotypic severity of C-CH is different, even in siblings. Importantly, an IGSF1 deficiency may result in severe hypothyroidism during the neonatal period.

Context: IGSF1 deficiency is a recently discovered syndrome consisting of congenital central hypothyroidism (CeH) and macroorchidism. Here, we report on a patient presenting with short stature, who was found to carry a pathogenic mutation in the IGSF1 gene. Case Description: A 14-year-old Israeli boy was referred to the Academic Medical Center in Amsterdam, The Netherlands, for follow-up on short stature ascribed to constitutional delay of growth and puberty, and familial hypercholesterolemia. Primary hypothyroidism had previously been excluded by a normal thyroid-stimulating hormone (TSH) concentration. However, in follow-up, plasma free thyroxine (FT4) concentrations were repeatedly low, and the patient was diagnosed with CeH. Because of coexistent relative macroorchidism, IGSF1 gene analysis was performed, revealing a mutation (c.2588C>G; p.Ser863Cys). The mutant IGSF1 protein was retained mainly in the endoplasmic reticulum and reached the plasma membrane with poor efficiency compared with wild-type protein. After starting thyroxine treatment, plasma cholesterol almost normalized. Conclusions: This case illustrates the necessity of measuring both FT4 and TSH when hypothyroidism is suspected, or needs to be ruled out. In addition, this case suggests that the presence of childhood hypercholesterolemia may be an indication of undiagnosed hypothyroidism., A teenager’s diagnosis of constitutional growth delay and hypercholesterolemia was corrected to central hypothyroidism because of IGSF1 deficiency syndrome. Levothyroxine improved both growth and lipids.

An insufficient stimulation by thyrotropin (TSH) of an otherwise normal thyroid gland represents the cause of Central Hypothyrodism (CeH). CeH is about 1000-folds rarer than Primary Hypothyroidism and often represents a real challenge for the clinicians, mainly because they cannot rely on adequately sensitive parameters for diagnosis or management, as it occurs with circulating TSH in PH. Therefore, CeH diagnosis can be frequently missed or delayed in patients with a previously unknown pituitary involvement. A series of genetic defects have been described to account for isolated CeH or combined pituitary hormone defects (CPHDs) with variable clinical characteristics and degrees of severity. The recently identified candidate gene IGSF1 appears frequently involved. This review provides an updated illustration of the different genetic defects accounting for CeH.

Growth hormone deficiency (GHD) may result from a failure of hypothalamic GHRH production or release, from congenital disorders of pituitary development, or from central nervous system insults including tumors, surgery, trauma, radiation or infiltration from inflammatory diseases. Idiopathic, isolated GHD is the most common sporadic form of hypopituitarism. GHD may also occur in combination with other pituitary hormone deficiencies, and is often referred to as hypopituitarism, combined pituitary hormone deficiency (CPHD), multiple pituitary hormone deficiency (MPHD) or panhypopituitarism. Children without any identifiable cause of their GHD are commonly labeled as having idiopathic hypopituitarism. MRI imaging is the technique of choice in the diagnosis of children with hypopituitarism. Marked differences in MRI pituitary gland morphology suggest different etiologies of GHD and different prognoses. Pituitary stalk agenesis and ectopic posterior pituitary (EPP) are specific markers of permanent GHD, and patients with these MRI findings show a different clinical and endocrine outcome compared to those with normal pituitary anatomy or hypoplastic pituitary alone. Furthermore, the classic triad of ectopic posterior pituitary gland, pituitary stalk hypoplasia/agenesis, and anterior pituitary gland hypoplasia is generally associated with permanent GHD. T2 DRIVE images aid in the identification of pituitary stalk without the use of contrast medium administration. Future developments in imaging techniques will undoubtedly reveal additional insights. Mutations in a number of genes encoding transcription factors - such as HESX1, SOX2, SOX3, LHX3, LHX4, PROP1, POU1F1, PITX, GLI3, GLI2, OTX2, ARNT2, IGSF1, FGF8, FGFR1, PROKR2, PROK2, CHD7, WDR11, NFKB2, PAX6, TCF7L1, IFT72, GPR161 and CDON - have been associated with pituitary dysfunction and abnormal pituitary gland development; the correlation of genetic mutations to endocrine and MRI phenotypes has improved our knowledge of pituitary development and management of patients with hypopituitarism, both in terms of possible genetic counseling, and of early diagnosis of evolving anterior pituitary hormone deficiencies.

Loss-of-function mutations of IGSF1 are an X-linked cause of central hypothyroidism (CeH) and hypoprolactinemia. A boy who is now 15.2 years old presented at the age of 7.69 years for evaluation of obesity. Previous thyroid function evaluation suggested CeH [FT4 0.6 ng/mL, thyroid-stimulating hormone (TSH) 2.2 mIU/L] but his physician took no action. At presentation he was clinically and biochemically euthyroid, prepubertal and obese. Serum prolactin (PRL) was undetectable. Biochemistry was normal except for mild hypercholesterolemia, total cholesterol 198 mg/dL. Subsequently FT4 and TSH levels fluctuated between 0.72-0.95 ng/dL (normal 0.8-2.0) and 1.94-5.77 mIU/L (normal 0.3-5.0), respectively. Sequencing of IGSF1 gene revealed a novel genetic change c.3805C>T in exon 19; substitution of amino acid Arginine at position 1269 with a premature «stop» codon resulting in an altered protein product. The patient additionally presented delayed adrenarche, low height velocity that resolved spontaneously and normal pubertal onset associated with increased FSH levels. At 14 years-of-age, while the patient was at Tanner stage 4, PRL levels became detectable, rising gradually to 2.3 ng/mL at last examination. Thyroxine replacement therapy resulted in decrease in total cholesterol 103 mg/dL. A high index of suspicion for the disorder is needed since several measurements of thyroid function may be required for CeH to be disclosed. The patient’s normal FT4 levels and normal intelligence would have resulted in a missed diagnosis if the serum PRL levels had not been measured. This case highlights the importance of measuring PRL in a boy with low normal FT4 and normal TSH levels.

Inhibins are gonadal hormones that suppress follicle-stimulating hormone (FSH) synthesis by pituitary gonadotrope cells. The structurally related activins stimulate FSH by signaling through complexes of type I and type II receptors. Two models of inhibin action were proposed in 2000. First, inhibins function as competitive receptor antagonists, binding activin type II receptors with high affinity in the presence of the TGF-β type III coreceptor, betaglycan. Second, immunoglobulin superfamily, member 1 (IGSF1, then called p120) was proposed to mediate inhibin B antagonism of activin signaling via its type I receptor. These ideas have been challenged over the past few years. Rather than playing a role in inhibin action, IGSF1 is involved in the central control of the thyroid gland. Betaglycan binds inhibin A and inhibin B with high affinity, but only functions as an obligate inhibin A coreceptor in murine gonadotropes. There is likely to be a distinct, but currently unidentified coreceptor for inhibin B.

We describe an overgrowth condition associated with X-linked copy number variation. Three brothers displayed an overgrowth pattern at birth that continued postnatally. Clinical findings included macrocephaly, distinctive facial features, developmental delay and variable clubfoot. Normal fetal growth was noted until the third trimester by Hadlock standards, revealing a late gestational overgrowth pattern. Microarray analysis in the family showed a maternally inherited 680 kb copy number duplication at Xq26.1-q26.2 in all three brothers. Molecular sequencing for known overgrowth conditions including GPC3, Sotos 1 (NSD1), Malan (NFIX), Perlman (DIS3L2), Weaver (EZH2), Opitz-Kaveggia (MED12) loci were negative. BWS IC1 and IC2 methylation and CDKN1C testing was also negative. Normal IGF1 levels excluded X-linked acrogiantism. The duplicated region Xq26.1-q26.2 contained IGSF1 and at least part of the lncRNA FIRRE. IGSF1, a highly expressed pituitary immunoglobulin superfamily gene, was recently implicated in a genome-wide association study of canine size. IGSF1 variants were associated with large canine breeds compared to smaller breeds. Our findings support the hypothesis that an X-linked variant encompassing the IGSF1 region may be associated with body size. Although IGSF1 loss has been noted in human hypothyroidism, this is the first reported phenotype in a family with copy number duplication in the region. Our findings suggest that prenatal evaluation, cross-species evaluation, Mendelian, and GWAS studies may describe a distinctive familial condition and its corresponding phenotypic features.

Loss of function mutations in the human X-linked immunoglobulin superfamily, member 1 (IGSF1) gene result in central hypothyroidism, often associated with macroorchidism. Igsf1-deficient mice are also centrally hypothyroid due to impaired TRH action in the pituitary. The mechanisms underlying macroorchidism are unclear and disputed. IGSF1 was originally characterized as an inhibin B co-receptor. As inhibin B negatively regulates FSH secretion, it was hypothesized that loss of IGSF1 would impair inhibin B action, leading to elevated FSH levels and enhanced Sertoli cell proliferation during development. Yet, in direct contradiction to this model, IGSF1 does not bind inhibin A or B in heterologous binding assays. Our preliminary data further indicate that FSHβ subunit (Fshb) mRNA expression is similarly antagonized by inhibin A and B in pituitary cultures from wild-type and Igsf1-deficient mice. More recently, IGSF1 was proposed to inhibit activin type IB receptor (ALK4) signaling. As activins stimulate FSH, loss of this inhibition should lead to increased FSH. However, neither humans nor mice with IGSF1-deficiency have elevated FSH and IGSF1 expression in FSH-producing gonadotrope cells is negligible. Additionally, Igsf1-deficient mice have normal serum LH and inhibin B levels, as well as testicular weights, histology, and semen parameters. Previous methods used to demonstrate IGSF1 regulation of a human FSHB promoter-reporter were conducted in a heterologous system in which such reporters lack activin/ALK4-dependent activity. We demonstrate that overexpression of IGSF1 in homologous LβT2 gonadotrope-like cells does not impair induction of murine or human Fshb/FSHB promoter-reporters by activin A or a constitutively active form of ALK4. Collectively, the available data fail to support a role for IGSF1 in FSH regulation by activins, inhibins, or otherwise.

Loss of function mutations in the X-linked immunoglobulin superfamily, member 1 (IGSF1) gene cause congenital central hypothyroidism, hypoprolactinemia, macroorchidism, and the dysregulation of growth hormone and pubertal development. IGSF1 is a type 1 transmembrane protein of unknown function that is highly expressed in the pituitary gland, choroid plexus, and developing liver. The mature form of the protein contains seven extracellular Ig loops, a single transmembrane domain, and a short intracellular carboxyl tail rich in serine and threonine residues. Although the function of IGSF1 is presently unknown, the topology of the protein suggests that it plays a role in intercellular communication. Two Igsf1 knockout mouse models exhibit reduced pituitary TRH receptor (Trhr1) expression and associated impairments in TRH-stimulated TSH secretion. How the loss of IGSF1 leads to reductions in Trhr1 levels is unresolved. We hypothesize that IGSF1 acts in concert with intracellular signaling molecules to regulate Trhr1 expression. To date, IGSF1 has been shown to interact with only two proteins, itself and the thyroid hormone transporter MCT8. However, MCT8 has low expression in the pituitary and IGSF1 does not alter MCT8-dependent thyroid hormone transport. Therefore, we implemented a new proximity labelling method, BioID, to characterize the intracellular IGSF1 interactome and ultimately determine IGSF1’s role in Trhr1 regulation. We expressed an IGSF1-BirA* fusion protein in heterologous cells and confirmed that it properly traffics to the plasma membrane. Moreover, the protein auto-biotinylates and labels other, currently unidentified proteins. IGSF1-BirA* maintains its ability to interact with MCT8, but does not interact with an intracellular signaling protein recently implicated in central hypothyroidism, insulin receptor substrate 4 (IRS4). We are stably expressing IGSF1-BirA* in heterologous and homologous cell lines, HEK293 and HepG2 (human hepatocellular carcinoma), respectively, for the BioID screen. We will purify biotinylated proteins and identify them using mass spectrometry. In follow-up analyses, we will focus on proteins that link IGSF1 to known signaling pathways.

Context Congenital isolated TSH deficiency (i-TSHD) is a rare form of congenital hypothyroidism. Five genes (IGSF1, IRS4, TBL1X, TRHR, and TSHB) responsible for the disease have been identified, although their relative frequencies and hypothalamic/pituitary unit phenotypes have remained to be clarified. Objectives To define the relative frequencies and hypothalamic/pituitary unit phenotypes of congenital i-TSHD resulting from single gene mutations. Patients and Methods Thirteen Japanese patients (11 boys and 2 girls) with congenital i-TSHD were enrolled. IGSF1, IRS4, TBL1X, TRHR, and TSHB were sequenced. For a TBL1X mutation (p.Asn382del), its pathogenicity was verified in vitro. For a literature review, published clinical data derived from 74 patients with congenital i-TSHD resulting from single-gene mutations were retrieved and analyzed. Results Genetic screening of the 13 study subjects revealed six mutation-carrying patients (46%), including five hemizygous IGSF1 mutation carriers and one hemizygous TBL1X mutation carrier. Among the six mutation carriers, one had intellectual disability and the other one had obesity, but the remaining four did not show nonendocrine phenotypes. Loss of function of the TBL1X mutation (p.Asn382del) was confirmed in vitro. The literature review demonstrated etiology-specific relationship between serum prolactin (PRL) levels and TRH-stimulated TSH levels with some degree of overlap. Conclusions The mutation screening study covering the five causative genes of congenital i-TSHD was performed, showing that the IGSF1 defect was the leading genetic cause of the disease. Assessing relationships between serum PRL levels and TRH-stimulated TSH levels would contribute to predict the etiologies of congenital i-TSHD.