DOI 10.1515/jpem-2013-0284 J Pediatr Endocr Met 2014; 27(5-6): 561–564
Patient report Ángela Domínguez-García, Rosa Martínez, Inés Urrutia, Intza Garin and Luis Castaño*
Identification of a novel insulin receptor gene heterozygous mutation in a patient with type A insulin resistance syndrome Abstract Background: Several types of mutations in the insulin receptor gene have been identified in patients with genetic syndromes of insulin resistance. Patient report: We describe a 12-year-old girl with type A insulin resistance with hyperandrogenism, hyperinsulinemia, and diabetes mellitus but without the dysmorphic characteristic of leprechaunism or Rabson-Mendenhall syndrome. The proband’s mother had hyperinsulinemia and diabetes mellitus but did not show any common clinical features of type A insulin resistance. The proband’s brother also had hyperinsulinemia but manifested neither glucose intolerance nor common clinical features of type A insulin resistance. A novel heterozygous mutation, p.Asn1164Thr, of the insulin receptor gene (INSR) was identified in this family. Conclusion: These cases illustrate the diversity of clinical phenotypes associated with mutations of the insulin receptor gene. Keywords: heterozygous mutation; insulin receptor gene; type A insulin resistance. *Corresponding author: Luis Castaño, MD, PhD, Endocrinology and Diabetes Research Group, Biocruces Health Research Institute, Cruces University Hospital, UPV-EHU, CIBERDEM, Plaza de Cruces s/n, 48903 Barakaldo, Spain, Phone: +34-946006099, E-mail: [email protected] Ángela Domínguez-García: Pediatric Endocrinology Unit, Insular Maternal and Child University Hospital Complex of Las Palmas, Las Palmas, Spain Rosa Martínez, Inés Urrutia and Intza Garin: Endocrinology and Diabetes Research Group, Biocruces Health Research Institute, Cruces University Hospital, UPV-EHU, CIBERDEM, Barakaldo, Spain
Introduction Mutations in the insulin receptor gene (INSR) lead to several forms of insulin resistance (IR). The human insulin receptor is a tetramer composed of two α and two β subunits linked together by disulfide bonds and is encoded by a single gene on chromosome 19 with 22 exons (1). The α chains contribute to the formation of the ligand-binding domain, while the β chains carry the kinase domain. Molecular genetic studies have identified various mutations in the human insulin receptor gene (2, 3). In addition, different clinical phenotypes have been identified: homozygous or compound-heterozygous mutations in the INSR are found in patients with syndromes of severe IR such as leprechaunism and Rabson-Mendenhall syndrome, whereas heterozygous mutations are found in milder syndromes such as type A IR. Severe IR, acanthosis nigricans (AN), and hyperandrogenism, in the absence of obesity or lipoatrophy, define type A IR syndrome (4). We describe the case of a non-obese 12-year-old girl who had AN, severe hyperandrogenemia, hormonal features of polycystic ovary syndrome, and profound IR but not clinical lipodystrophy. On the basis of these characteristics, type A IR syndrome was diagnosed. We identified a heterozygous mutation, p.Asn1164Thr, in the INSR that may affect the kinase domain.
Patient report The proband, a 12-year-old white girl from the Canary Islands, was referred to the Pediatric Endocrinology Unit in Las Palmas with severe AN and hirsutism. Her weight was 39.3 kg, height 149 cm [body mass index (BMI), 17.3 kg/m2], and breasts were at Tanner stage 3. Her birth weight was normal and spontaneous thelarche occurred at age 11 years, but menarche had not occurred and she
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562 Domínguez-García et al.: Clinical heterogeneity type A insulin resistance did not have premature pubarche. Physical examination revealed an android body type with moderate excess hair on the upper lip and midline of the lower abdominal wall. She was assessed as having a Ferriman-Gallwey score of 10 (average 5). Evidence of AN was observed in the axillae and neck. The waist-to-hip circumference ratio was normal. Neither lipoatrophy of the limbs nor fat accumulation in the face and neck region was observed. Examination of the genitalia disclosed a mildly enlarged clitoris. No abnormalities were detected in neuromuscular, cardiac, or cutaneous examinations. Hormonal tests showed normal levels of serum dehydroepiandrosterone sulfate (40.8 μg/dL, reference range 35–430) and free testosterone (2.5 pg/mL, reference range 0.04–3.9) but elevated levels of androstenedione (7 ng/mL, reference range 0.4–2.7). The plasma sex hormone-binding globulin level (measured with an immunoradiometric assay) was low. The basal plasma estradiol concentration was normal; however, levels of this hormone were elevated in the gonadotropin-releasing hormone (GnRH)-stimulated state (1246 pg/mL). The ratio of luteinizing hormone to follicle-stimulating hormone was high, both in the basal and GnRH-stimulated states. However, the levels of serum prolactin, plasma and urinary free cortisol, and basal and corticotropin-stimulated (0.25 mg i.v.) 17-hydroxyprogesterone were normal, as were the pituitary-adrenal and pituitary-thyroid axis functions. The level of adiponectin was also normal (15.9 μg/mL, reference range 7.1–19.3). No abnormalities were detected by computed tomography of the abdomen. Pelvic sonography showed a normal uterus, with linear endometrium but without polycystic ovaries. The karyotype was 46XX. A standard 75-g oral glucose tolerance test (OGTT) was performed, after a 12-h overnight fast, to assess plasma glucose and insulin levels (measured with an immunoradiometric assay) (Table 1). The patient was found to be markedly insulin resistant and had diabetes mellitus. Severe fasting hyperinsulinemia was reproducibly observed, and the homeostasis model assessment
of IR (HOMA-IR) index was 38.29. The test for circulating insulin receptor autoantibodies (measured with an enzyme immunoassay by the reference laboratory) was negative. The HbA1c (29 mmol/mol, 4.8%), serum total cholesterol, and triglyceride levels were normal, as were the kidney and liver function test results. Bone age was 14 years, and bone densitometry was normal. The proband’s mother, brother 1, brother 2, and brother 3 were asymptomatic; did not have AN; and were not obese, bald, or lypodystrophic. OGTTs were performed on these four family members (Table 1). The proband’s mother was shown to be insulin resistant and had diabetes mellitus, brother 1 was also insulin resistant but did not have altered glucose tolerance, and brothers 2 and 3 were not insulin resistant. The patient received therapy with metformin (an oral antidiabetic drug) to increase insulin sensitivity, with little beneficial effect on plasma insulin levels (postmetformin insulin level, 101.7 μU/mL), and combined oral contraceptive treatment that induced cyclical withdrawal bleeding; however, amenorrhea recurred after the interruption of this treatment. During the past 5 years, the HbA1c and the fasting plasma glucose levels in the patient (with metformin) and in her mother (untreated) have remained normal, although post-OGTT levels have been elevated. Informed consent was obtained from the mother, and mutation analysis was performed through amplification of the 22 exons and flanking intron regions of the INSR gene by PCR (primer sequences and conditions are available on request from the authors) and sequencing in both directions using the Big Dye Terminator v3.1 sequencing kit (Applied Biosystems, Austin, Texas, USA) on an ABI 3130xl DNA sequencer system (Applied Biosystems). All sequences were analyzed and compared with the wild-type published reference sequence (GenBank NM_000208.2, NP_000199.2) of the transcript variant 1 (the long preproprotein) with the ABI Seqscape software v2.5 (Applied Biosystems).
Table 1 Clinical characteristics of the patient with type A insulin resistance and her family.
Patient
Mother
Brother 1
Brother 2
Brother 3
Glucose at 0 min, mg/dL Glucose at 120 min, mg/dLa Insulin at 0 min, μU/mL Insulin at 120 min, μU/mL HOMA-IR
85 225 182 > 1000 38.29
90 271 137 – 30.4
83 139 50.7 – 10.4
90 102 12.9 – 2.3
93 83 2.9 – 0.5
a Blood glucose after oral glucose tolerance test (OGTT); HOMA-IR, homeostasis model assessment of insulin resistance. Note: To convert mg/dL to mmol/L for glucose, multiply by 0.05551; to convert μU/mL to pmol/L for insulin, multiply by 7.175.
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Domínguez-García et al.: Clinical heterogeneity type A insulin resistance 563
Direct sequencing analysis revealed that the proband was heterozygous for a novel missense mutation in exon 19 of the INSR gene in which asparagine is substituted by threonine in codon 1164 (p.Asn1164Thr, c.3491A > C). The proband’s mother and brother 1 were also heterozygous for the mutation. This mutation was not present in 96 Spanish control individuals and has not been reported in the literature, or in the HGMD, dbSNP, and 1000 Genomes databases. Further, the Asn1164 residue is highly conserved across species, from mammals to zebrafish and Xenopus, and in silico analysis (PolyPhen-2: http://genetics.bwh. harvard.edu/pph2/, SIFT: http://sift-dna.org, and Panther: http://www.pantherdb.org/tools/csnpScoreForm.jsp) suggests that the mutation p.Asn1164Thr is likely to be pathogenic. That is, the conservation of the Asn residue across species, the absence of the mutation in control chromosomes, and software analysis all indicate that this mutation is pathogenic; however, functional studies are necessary to confirm our hypothesis.
Discussion The patient described herein was referred with AN (linked to a marked IR) and hirsutism. These findings, characteristic of type A IR syndrome, in a non-obese girl led us to search for mutations or circulating autoantibodies affecting the insulin receptor (4–6). However, there is no distinctive serum marker, and therefore, the diagnosis of these patients is not straightforward. The clinical evaluation of IR is based on several tests, including the determination of insulin levels (7). The criteria proposed for diagnosing IR in non-diabetic individuals with BMI 150 pmol/L and/or a peak insulin in an OGTT of > 1500 pmol/L (8). All IR syndromes share a number of laboratory findings, among which hyperinsulinemia is the most consistent (4, 6, 9). Additionally, impaired glucose tolerance or frank diabetes mellitus appears commonly but not always (2, 4, 6, 9). In our case, the patient and
her mother had normal fasting glucose levels and diabetes mellitus was only diagnosed after an OGTT, whereas brother 1 had hyperinsulinemia but did not have altered glucose tolerance. The proband also showed AN and hyperandrogenism, although her mother and brother did not. These observations indicate that there is a variable expression of the disease in the affected family members, although the p.Asn1164Thr mutation does impair insulin receptor function as reflected by the hyperinsulinemia and glucose intolerance of the mother. The heterogeneity in the phenotypic expression of different heterozygous mutations in the INSR within a family has also been described by other authors (10, 11). Heterozygous mutations in the INSR usually result in a less severe phenotype such as type A IR (12), although compound heterozygous (13–15) or homozygous (16) mutations of the INSR have also been detected in individuals with type A IR. The Asn1164 residue is located in the tyrosine kinase domain in the intracellular β-subunit of the insulin receptor. Different mutations in the kinase region of the insulin receptor (16–18) have been reported to interfere with transmembrane signaling by compromising receptor tyrosine kinase activity (19, 20). In conclusion, we identified a new heterozygous missense mutation in the INSR gene (p.Asn1164Thr) in a patient with type A IR syndrome. The phenotype of this mutation in this family was variable and illustrates the diversity of clinical phenotypes associated with mutations of the insulin receptor gene. Acknowledgments: This work was partially funded by Research Project grants from the Instituto de Salud Carlos III of the Spanish Ministry of Health (PS09/01492), from the Basque Departments of Health (GV2010111185), and from the University of Basque Country (IT-472-07). Conflict of interest statement Competing interests: None declared. Received July 3, 2013; accepted December 2, 2013; previously published online January 27, 2014
References 1. Cheatham B, Kahn CR. Insulin action and the insulin signaling network. Endocr Rev 1995;16:117–42. 2. Longo N, Wang Y, Smith SA, Langley SD, DiMeglio LA, et al. Genotype-phenotype correlation in inherited severe insulin resistance. Hum Mol Genet 2002;11:1465–75.
3. Taylor SI, Cama A, Accili D, Barbetti F, Quon MJ, et al. Mutations in the insulin receptor gene. Endocr Rev 1992;13:566–95. 4. Kahn CR, Flier JS, Bar RS, Archer JA, Gorden P, et al. The syndromes of insulin resistance and acanthosis nigricans: insulin-receptor disorders in man. N Engl J Med 1976;294:739–45.
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564 Domínguez-García et al.: Clinical heterogeneity type A insulin resistance 5. Simonson GD, Kendall DM. Diagnosis of insulin resistance and associated syndromes: the spectrum from the metabolic syndrome to type 2 diabetes mellitus. Coron Artery Dis 2005;16:465–72. 6. Mantzoros CS, Flier JS. Insulin resistance: the clinical spectrum. In: Mazzaferi E, editor. Advances in endocrinology and metabolism. vol. 6. St. Louis: Mosby-Year Book, 1995:193–232. 7. Vidal-Puig A, Moller DE. Insulin resistance: classification, prevalence, clinical manifestations, and diagnosis. In: Azziz R, Nestler JE, Dewailly D, editors. Androgen excess disorders in women. Philadelphia: Lippincott Raven, 1997:227–36. 8. Semple RK, Savage DB, Cochran EK, Gorden P, O’Rahilly S. Genetic syndromes of severe insulin resistance. Endocr Rev 2011;32:498–514. 9. Ten S, Maclaren N. Insulin resistance syndrome in children. J Clin Endocrinol 2004;89:2526–9. 10. Takahashi I, Yamada Y, Kadowaki H, Horikoshi M, Kadowaki T, et al. Phenotypical variety of insulin resistance in a family with a novel mutation of the insulin receptor gene. Endocrine J 2010;57:509–16. 11. Huang Z, Li Y, Tang T, Xu W, Liao Z, et al. Hyperinsulinemaemic hypoglycaemia associated with a heterozygous missense mutation of R1174W the insulin receptor gene. Clin Endocrinol J 2009;71:659–65. 12. Musso C, Cochran E, Moran SA, Skarulis MC, Oral EA, et al. Clinical course of genetic diseases of the insulin receptor (type A and Rabson-Mendenhall syndromes): a 30-year prospective. Medicine (Baltimore) 2004;83:209–22. 13. Hashiramoto M, Osawa H, Ando M, Murakami A, Nishimiya T, et al. A nonsense mutation in the Arg345 of the insulin receptor
gene in a Japanese type A insulin-resistant patient. Endocr J 2005;52:499–504. 14. Kadowaki T, Kadowaki H, Rechler MM, Serrano-Rios M, Roth J, et al. Five mutant alleles of the insulin receptor gene in patients with genetic forms of insulin resistance. J Clin Invest 1990;86:254–64. 15. Ogawa W, Iwamoto K, Mori H, Hashiramoto M, Miyake K, et al. Two related cases of type A insulin resistance with compound heterozygous mutations of the insulin receptor gene. Diabetes Res Clin Pract 2009;83:e75–7. 16. Maassen JA, Tobias ES, Kayserilli H, Tukel T, Yuksel-Apak M, et al. Identification and functional assessment of novel and known insulin receptor mutations in five patients with syndromes of severe insulin resistance. J Clin Endocrinol Metab 2003;88:4251–7. 17. Moller DE, Cohen O, Yamaguchi Y, Assiz R, Grigorescu F, et al. Prevalence of mutations in the insulin receptor gene in subjects with features of the type A syndrome of insulin resistance. Diabetes 1994;43:247–55. 18. Iwanishi M, Haruta T, Takata Y, Ishibashi O, Sasaoka T, et al. A mutation (Trp1193→Leu1193) in the tyrosine kinase domain of the insulin receptor associated with type A syndrome of insulin resistance. Diabetologia 1993;36:414–22. 19. Takahashi Y, Kadowaki H, Momomura K, Fukushima Y, Orban T, et al. A homozygous kinase-defective mutation in the insulin receptor gene in a patient with leprechaunism. Diabetologia 1997;40:412–20. 20. Moller DE, Yokota A, White MF, Pazianos AG, Flier JS. A naturally occurring mutation of insulin receptor alanine 1134 impairs tyrosine kinase function and is associated with dominantly inherited insulin resistance. J Biol Chem 1990;265:14979–85.
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Patient report Ángela Domínguez-García, Rosa Martínez, Inés Urrutia, Intza Garin and Luis Castaño*
Identification of a novel insulin receptor gene heterozygous mutation in a patient with type A insulin resistance syndrome Abstract Background: Several types of mutations in the insulin receptor gene have been identified in patients with genetic syndromes of insulin resistance. Patient report: We describe a 12-year-old girl with type A insulin resistance with hyperandrogenism, hyperinsulinemia, and diabetes mellitus but without the dysmorphic characteristic of leprechaunism or Rabson-Mendenhall syndrome. The proband’s mother had hyperinsulinemia and diabetes mellitus but did not show any common clinical features of type A insulin resistance. The proband’s brother also had hyperinsulinemia but manifested neither glucose intolerance nor common clinical features of type A insulin resistance. A novel heterozygous mutation, p.Asn1164Thr, of the insulin receptor gene (INSR) was identified in this family. Conclusion: These cases illustrate the diversity of clinical phenotypes associated with mutations of the insulin receptor gene. Keywords: heterozygous mutation; insulin receptor gene; type A insulin resistance. *Corresponding author: Luis Castaño, MD, PhD, Endocrinology and Diabetes Research Group, Biocruces Health Research Institute, Cruces University Hospital, UPV-EHU, CIBERDEM, Plaza de Cruces s/n, 48903 Barakaldo, Spain, Phone: +34-946006099, E-mail: [email protected] Ángela Domínguez-García: Pediatric Endocrinology Unit, Insular Maternal and Child University Hospital Complex of Las Palmas, Las Palmas, Spain Rosa Martínez, Inés Urrutia and Intza Garin: Endocrinology and Diabetes Research Group, Biocruces Health Research Institute, Cruces University Hospital, UPV-EHU, CIBERDEM, Barakaldo, Spain
Introduction Mutations in the insulin receptor gene (INSR) lead to several forms of insulin resistance (IR). The human insulin receptor is a tetramer composed of two α and two β subunits linked together by disulfide bonds and is encoded by a single gene on chromosome 19 with 22 exons (1). The α chains contribute to the formation of the ligand-binding domain, while the β chains carry the kinase domain. Molecular genetic studies have identified various mutations in the human insulin receptor gene (2, 3). In addition, different clinical phenotypes have been identified: homozygous or compound-heterozygous mutations in the INSR are found in patients with syndromes of severe IR such as leprechaunism and Rabson-Mendenhall syndrome, whereas heterozygous mutations are found in milder syndromes such as type A IR. Severe IR, acanthosis nigricans (AN), and hyperandrogenism, in the absence of obesity or lipoatrophy, define type A IR syndrome (4). We describe the case of a non-obese 12-year-old girl who had AN, severe hyperandrogenemia, hormonal features of polycystic ovary syndrome, and profound IR but not clinical lipodystrophy. On the basis of these characteristics, type A IR syndrome was diagnosed. We identified a heterozygous mutation, p.Asn1164Thr, in the INSR that may affect the kinase domain.
Patient report The proband, a 12-year-old white girl from the Canary Islands, was referred to the Pediatric Endocrinology Unit in Las Palmas with severe AN and hirsutism. Her weight was 39.3 kg, height 149 cm [body mass index (BMI), 17.3 kg/m2], and breasts were at Tanner stage 3. Her birth weight was normal and spontaneous thelarche occurred at age 11 years, but menarche had not occurred and she
Brought to you by | University of California - San Francisco Authenticated Download Date | 2/17/15 7:22 PM
562 Domínguez-García et al.: Clinical heterogeneity type A insulin resistance did not have premature pubarche. Physical examination revealed an android body type with moderate excess hair on the upper lip and midline of the lower abdominal wall. She was assessed as having a Ferriman-Gallwey score of 10 (average 5). Evidence of AN was observed in the axillae and neck. The waist-to-hip circumference ratio was normal. Neither lipoatrophy of the limbs nor fat accumulation in the face and neck region was observed. Examination of the genitalia disclosed a mildly enlarged clitoris. No abnormalities were detected in neuromuscular, cardiac, or cutaneous examinations. Hormonal tests showed normal levels of serum dehydroepiandrosterone sulfate (40.8 μg/dL, reference range 35–430) and free testosterone (2.5 pg/mL, reference range 0.04–3.9) but elevated levels of androstenedione (7 ng/mL, reference range 0.4–2.7). The plasma sex hormone-binding globulin level (measured with an immunoradiometric assay) was low. The basal plasma estradiol concentration was normal; however, levels of this hormone were elevated in the gonadotropin-releasing hormone (GnRH)-stimulated state (1246 pg/mL). The ratio of luteinizing hormone to follicle-stimulating hormone was high, both in the basal and GnRH-stimulated states. However, the levels of serum prolactin, plasma and urinary free cortisol, and basal and corticotropin-stimulated (0.25 mg i.v.) 17-hydroxyprogesterone were normal, as were the pituitary-adrenal and pituitary-thyroid axis functions. The level of adiponectin was also normal (15.9 μg/mL, reference range 7.1–19.3). No abnormalities were detected by computed tomography of the abdomen. Pelvic sonography showed a normal uterus, with linear endometrium but without polycystic ovaries. The karyotype was 46XX. A standard 75-g oral glucose tolerance test (OGTT) was performed, after a 12-h overnight fast, to assess plasma glucose and insulin levels (measured with an immunoradiometric assay) (Table 1). The patient was found to be markedly insulin resistant and had diabetes mellitus. Severe fasting hyperinsulinemia was reproducibly observed, and the homeostasis model assessment
of IR (HOMA-IR) index was 38.29. The test for circulating insulin receptor autoantibodies (measured with an enzyme immunoassay by the reference laboratory) was negative. The HbA1c (29 mmol/mol, 4.8%), serum total cholesterol, and triglyceride levels were normal, as were the kidney and liver function test results. Bone age was 14 years, and bone densitometry was normal. The proband’s mother, brother 1, brother 2, and brother 3 were asymptomatic; did not have AN; and were not obese, bald, or lypodystrophic. OGTTs were performed on these four family members (Table 1). The proband’s mother was shown to be insulin resistant and had diabetes mellitus, brother 1 was also insulin resistant but did not have altered glucose tolerance, and brothers 2 and 3 were not insulin resistant. The patient received therapy with metformin (an oral antidiabetic drug) to increase insulin sensitivity, with little beneficial effect on plasma insulin levels (postmetformin insulin level, 101.7 μU/mL), and combined oral contraceptive treatment that induced cyclical withdrawal bleeding; however, amenorrhea recurred after the interruption of this treatment. During the past 5 years, the HbA1c and the fasting plasma glucose levels in the patient (with metformin) and in her mother (untreated) have remained normal, although post-OGTT levels have been elevated. Informed consent was obtained from the mother, and mutation analysis was performed through amplification of the 22 exons and flanking intron regions of the INSR gene by PCR (primer sequences and conditions are available on request from the authors) and sequencing in both directions using the Big Dye Terminator v3.1 sequencing kit (Applied Biosystems, Austin, Texas, USA) on an ABI 3130xl DNA sequencer system (Applied Biosystems). All sequences were analyzed and compared with the wild-type published reference sequence (GenBank NM_000208.2, NP_000199.2) of the transcript variant 1 (the long preproprotein) with the ABI Seqscape software v2.5 (Applied Biosystems).
Table 1 Clinical characteristics of the patient with type A insulin resistance and her family.
Patient
Mother
Brother 1
Brother 2
Brother 3
Glucose at 0 min, mg/dL Glucose at 120 min, mg/dLa Insulin at 0 min, μU/mL Insulin at 120 min, μU/mL HOMA-IR
85 225 182 > 1000 38.29
90 271 137 – 30.4
83 139 50.7 – 10.4
90 102 12.9 – 2.3
93 83 2.9 – 0.5
a Blood glucose after oral glucose tolerance test (OGTT); HOMA-IR, homeostasis model assessment of insulin resistance. Note: To convert mg/dL to mmol/L for glucose, multiply by 0.05551; to convert μU/mL to pmol/L for insulin, multiply by 7.175.
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Domínguez-García et al.: Clinical heterogeneity type A insulin resistance 563
Direct sequencing analysis revealed that the proband was heterozygous for a novel missense mutation in exon 19 of the INSR gene in which asparagine is substituted by threonine in codon 1164 (p.Asn1164Thr, c.3491A > C). The proband’s mother and brother 1 were also heterozygous for the mutation. This mutation was not present in 96 Spanish control individuals and has not been reported in the literature, or in the HGMD, dbSNP, and 1000 Genomes databases. Further, the Asn1164 residue is highly conserved across species, from mammals to zebrafish and Xenopus, and in silico analysis (PolyPhen-2: http://genetics.bwh. harvard.edu/pph2/, SIFT: http://sift-dna.org, and Panther: http://www.pantherdb.org/tools/csnpScoreForm.jsp) suggests that the mutation p.Asn1164Thr is likely to be pathogenic. That is, the conservation of the Asn residue across species, the absence of the mutation in control chromosomes, and software analysis all indicate that this mutation is pathogenic; however, functional studies are necessary to confirm our hypothesis.
Discussion The patient described herein was referred with AN (linked to a marked IR) and hirsutism. These findings, characteristic of type A IR syndrome, in a non-obese girl led us to search for mutations or circulating autoantibodies affecting the insulin receptor (4–6). However, there is no distinctive serum marker, and therefore, the diagnosis of these patients is not straightforward. The clinical evaluation of IR is based on several tests, including the determination of insulin levels (7). The criteria proposed for diagnosing IR in non-diabetic individuals with BMI 150 pmol/L and/or a peak insulin in an OGTT of > 1500 pmol/L (8). All IR syndromes share a number of laboratory findings, among which hyperinsulinemia is the most consistent (4, 6, 9). Additionally, impaired glucose tolerance or frank diabetes mellitus appears commonly but not always (2, 4, 6, 9). In our case, the patient and
her mother had normal fasting glucose levels and diabetes mellitus was only diagnosed after an OGTT, whereas brother 1 had hyperinsulinemia but did not have altered glucose tolerance. The proband also showed AN and hyperandrogenism, although her mother and brother did not. These observations indicate that there is a variable expression of the disease in the affected family members, although the p.Asn1164Thr mutation does impair insulin receptor function as reflected by the hyperinsulinemia and glucose intolerance of the mother. The heterogeneity in the phenotypic expression of different heterozygous mutations in the INSR within a family has also been described by other authors (10, 11). Heterozygous mutations in the INSR usually result in a less severe phenotype such as type A IR (12), although compound heterozygous (13–15) or homozygous (16) mutations of the INSR have also been detected in individuals with type A IR. The Asn1164 residue is located in the tyrosine kinase domain in the intracellular β-subunit of the insulin receptor. Different mutations in the kinase region of the insulin receptor (16–18) have been reported to interfere with transmembrane signaling by compromising receptor tyrosine kinase activity (19, 20). In conclusion, we identified a new heterozygous missense mutation in the INSR gene (p.Asn1164Thr) in a patient with type A IR syndrome. The phenotype of this mutation in this family was variable and illustrates the diversity of clinical phenotypes associated with mutations of the insulin receptor gene. Acknowledgments: This work was partially funded by Research Project grants from the Instituto de Salud Carlos III of the Spanish Ministry of Health (PS09/01492), from the Basque Departments of Health (GV2010111185), and from the University of Basque Country (IT-472-07). Conflict of interest statement Competing interests: None declared. Received July 3, 2013; accepted December 2, 2013; previously published online January 27, 2014
References 1. Cheatham B, Kahn CR. Insulin action and the insulin signaling network. Endocr Rev 1995;16:117–42. 2. Longo N, Wang Y, Smith SA, Langley SD, DiMeglio LA, et al. Genotype-phenotype correlation in inherited severe insulin resistance. Hum Mol Genet 2002;11:1465–75.
3. Taylor SI, Cama A, Accili D, Barbetti F, Quon MJ, et al. Mutations in the insulin receptor gene. Endocr Rev 1992;13:566–95. 4. Kahn CR, Flier JS, Bar RS, Archer JA, Gorden P, et al. The syndromes of insulin resistance and acanthosis nigricans: insulin-receptor disorders in man. N Engl J Med 1976;294:739–45.
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564 Domínguez-García et al.: Clinical heterogeneity type A insulin resistance 5. Simonson GD, Kendall DM. Diagnosis of insulin resistance and associated syndromes: the spectrum from the metabolic syndrome to type 2 diabetes mellitus. Coron Artery Dis 2005;16:465–72. 6. Mantzoros CS, Flier JS. Insulin resistance: the clinical spectrum. In: Mazzaferi E, editor. Advances in endocrinology and metabolism. vol. 6. St. Louis: Mosby-Year Book, 1995:193–232. 7. Vidal-Puig A, Moller DE. Insulin resistance: classification, prevalence, clinical manifestations, and diagnosis. In: Azziz R, Nestler JE, Dewailly D, editors. Androgen excess disorders in women. Philadelphia: Lippincott Raven, 1997:227–36. 8. Semple RK, Savage DB, Cochran EK, Gorden P, O’Rahilly S. Genetic syndromes of severe insulin resistance. Endocr Rev 2011;32:498–514. 9. Ten S, Maclaren N. Insulin resistance syndrome in children. J Clin Endocrinol 2004;89:2526–9. 10. Takahashi I, Yamada Y, Kadowaki H, Horikoshi M, Kadowaki T, et al. Phenotypical variety of insulin resistance in a family with a novel mutation of the insulin receptor gene. Endocrine J 2010;57:509–16. 11. Huang Z, Li Y, Tang T, Xu W, Liao Z, et al. Hyperinsulinemaemic hypoglycaemia associated with a heterozygous missense mutation of R1174W the insulin receptor gene. Clin Endocrinol J 2009;71:659–65. 12. Musso C, Cochran E, Moran SA, Skarulis MC, Oral EA, et al. Clinical course of genetic diseases of the insulin receptor (type A and Rabson-Mendenhall syndromes): a 30-year prospective. Medicine (Baltimore) 2004;83:209–22. 13. Hashiramoto M, Osawa H, Ando M, Murakami A, Nishimiya T, et al. A nonsense mutation in the Arg345 of the insulin receptor
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![[Severe type A insulin resistance syndrome due to a mutation in the insulin receptor gene].](/assets/img/hold.png)
