CONICET | Buscador de Institutos y Recursos Humanos

ENDOCRINE AND IVillTABOLIC EFFECTS IN AClD-LAIHLE SUBUNIT DEFICIENCY. Domené H; Bengolea S; Martínez A; Ropelato M; Scaglia P; Pennisi P; Heinrich JJ; Jasper H. Division of Endocrinology, Endocrinology Research <;=enter(CEDIE), Children´s Hospi tal and Division ofPediatrics, JA FemáIldez Hospital, Buenós Aires, Argentina. IntroductÍGn: Tbe acid-labile subunit (ALS) is an 8S-kDa glycoprotein synthesized in the liver under the control of GH. ALS stabilizes IGF-I and IGFBP-3 in the circulation by the formation of 150-kDa temary complexes, reducing the passage of the lGFs to the extravascular compartment, and extending their half-life. We describe a 17-year old boy with delay of growth and pubertal development associated with a homozygous inactivating mutation in tbe IGFALS gene. the control of GH. ALS stabilizes IGF-I and IGFBP-3 in the circulation by the formation of 150-kDa temary complexes, reducing the passage of the lGFs to the extravascular compartment, and extending their half-life. We describe a 17-year old boy with delay of growth and pubertal development associated with a homozygous inactivating mutation in tbe IGFALS gene. Tbe acid-labile subunit (ALS) is an 8S-kDa glycoprotein synthesized in the liver under the control of GH. ALS stabilizes IGF-I and IGFBP-3 in the circulation by the formation of 150-kDa temary complexes, reducing the passage of the lGFs to the extravascular compartment, and extending their half-life. We describe a 17-year old boy with delay of growth and pubertal development associated with a homozygous inactivating mutation in tbe IGFALS gene. Mcthodology and Resulto: At 14.6 years height was 145.2 cm (-2.05 SDS), weight3S.9 kg (-2.34 SDS), Tanner stage 1,botb testes 3 mI. The GH response to provocative test was normal (31.0 ngl SDS), Tanner stage 1,botb testes 3 mI. The GH response to provocative test was normal (31.0 ngl At 14.6 years height was 145.2 cm (-2.05 SDS), weight3S.9 kg (-2.34 SDS), Tanner stage 1,botb testes 3 mI. The GH response to provocative test was normal (31.0 nglngl mI), but spontéU1eousnocturnal secretion was increased (l8.9±12.6 ng/rnl). Both basal IGF-I (31 nglngl 111]; -5.3 SDS) and IGFBP-3 (0.22 /lg/ml; -9.7 SDS) were low, éU1dALS was undetectable. An IGF-I generation test and a 6-month GH treatment period were ineffective to induce any changes in IGF-I, IGFBP-3, and ALS levels, as well as to improve growth ve]ocity. Sequencing of the complete coding region of tbe IGFALS gene revealed a homozygous mutation in exon 2 (1338delG; E35fsXI20). This frame-shifLing mutation predicts the formation of a truncaled, most likely inactive protein. Circulating ALS protein was undetectable by westem immunobloting using anLi-ALS antibodies. Incubation of sel1lm with 1251I_GF-l followed by cross-linking and éUlalyzedby size exclusion column chromatography revealed complete inability for temal)´ compJex formation. Oral glucose loads performed before and during GH treatment showed normal glucose ]evels with exaggerated insulin responses, indicatjng some degree of insulin resistance. A 3-month period of metformin treatment reduced basal insulin levels by 47% and insulin sensitivity index improves to 2.1, near to nonnal value. Conclusions: The lack of circulating ALS prevents the formation of the ternary complex, markedly decreases serum IGF-I and IGFBP-3, increases GH secretion, induces insulin resistance, éU1cp1robably causes pubertal del ay with minimal effect on linear growth. Tbese fjndings suggest that total circulating IGF-l would not be the major mediator of tbe growth-promoting actions of GH. Perhaps its main roles are the feedback control on GH secretiol1 éUldthe regulation of carbohydrates metabolism by facilitatinginsulin action. Further studies may reveal if lGFALS mutations could be involved in other cases of delay of growth and pubertal development in children. markedly decreases serum IGF-I and IGFBP-3, increases GH secretion, induces insulin resistance, éU1cp1robably causes pubertal del ay with minimal effect on linear growth. Tbese fjndings suggest that total circulating IGF-l would not be the major mediator of tbe growth-promoting actions of GH. Perhaps its main roles are the feedback control on GH secretiol1 éUldthe regulation of carbohydrates metabolism by facilitatinginsulin action. Further studies may reveal if lGFALS mutations could be involved in other cases of delay of growth and pubertal development in children. chromatography revealed complete inability for temal)´ compJex formation. Oral glucose loads performed before and during GH treatment showed normal glucose ]evels with exaggerated insulin responses, indicatjng some degree of insulin resistance. A 3-month period of metformin treatment reduced basal insulin levels by 47% and insulin sensitivity index improves to 2.1, near to nonnal value. Conclusions: The lack of circulating ALS prevents the formation of the ternary complex, markedly decreases serum IGF-I and IGFBP-3, increases GH secretion, induces insulin resistance, éU1cp1robably causes pubertal del ay with minimal effect on linear growth. Tbese fjndings suggest that total circulating IGF-l would not be the major mediator of tbe growth-promoting actions of GH. Perhaps its main roles are the feedback control on GH secretiol1 éUldthe regulation of carbohydrates metabolism by facilitatinginsulin action. Further studies may reveal if lGFALS mutations could be involved in other cases of delay of growth and pubertal development in children. markedly decreases serum IGF-I and IGFBP-3, increases GH secretion, induces insulin resistance, éU1cp1robably causes pubertal del ay with minimal effect on linear growth. Tbese fjndings suggest that total circulating IGF-l would not be the major mediator of tbe growth-promoting actions of GH. Perhaps its main roles are the feedback control on GH secretiol1 éUldthe regulation of carbohydrates metabolism by facilitatinginsulin action. Further studies may reveal if lGFALS mutations could be involved in other cases of delay of growth and pubertal development in children. generation test and a 6-month GH treatment period were ineffective to induce any changes in IGF-I, IGFBP-3, and ALS levels, as well as to improve growth ve]ocity. Sequencing of the complete coding region of tbe IGFALS gene revealed a homozygous mutation in exon 2 (1338delG; E35fsXI20). This frame-shifLing mutation predicts the formation of a truncaled, most likely inactive protein. Circulating ALS protein was undetectable by westem immunobloting using anLi-ALS antibodies. Incubation of sel1lm with 1251I_GF-l followed by cross-linking and éUlalyzedby size exclusion column chromatography revealed complete inability for temal)´ compJex formation. Oral glucose loads performed before and during GH treatment showed normal glucose ]evels with exaggerated insulin responses, indicatjng some degree of insulin resistance. A 3-month period of metformin treatment reduced basal insulin levels by 47% and insulin sensitivity index improves to 2.1, near to nonnal value. Conclusions: The lack of circulating ALS prevents the formation of the ternary complex, markedly decreases serum IGF-I and IGFBP-3, increases GH secretion, induces insulin resistance, éU1cp1robably causes pubertal del ay with minimal effect on linear growth. Tbese fjndings suggest that total circulating IGF-l would not be the major mediator of tbe growth-promoting actions of GH. Perhaps its main roles are the feedback control on GH secretiol1 éUldthe regulation of carbohydrates metabolism by facilitatinginsulin action. Further studies may reveal if lGFALS mutations could be involved in other cases of delay of growth and pubertal development in children. markedly decreases serum IGF-I and IGFBP-3, increases GH secretion, induces insulin resistance, éU1cp1robably causes pubertal del ay with minimal effect on linear growth. Tbese fjndings suggest that total circulating IGF-l would not be the major mediator of tbe growth-promoting actions of GH. Perhaps its main roles are the feedback control on GH secretiol1 éUldthe regulation of carbohydrates metabolism by facilitatinginsulin action. Further studies may reveal if lGFALS mutations could be involved in other cases of delay of growth and pubertal development in children. chromatography revealed complete inability for temal)´ compJex formation. Oral glucose loads performed before and during GH treatment showed normal glucose ]evels with exaggerated insulin responses, indicatjng some degree of insulin resistance. A 3-month period of metformin treatment reduced basal insulin levels by 47% and insulin sensitivity index improves to 2.1, near to nonnal value. Conclusions: The lack of circulating ALS prevents the formation of the ternary complex, markedly decreases serum IGF-I and IGFBP-3, increases GH secretion, induces insulin resistance, éU1cp1robably causes pubertal del ay with minimal effect on linear growth. Tbese fjndings suggest that total circulating IGF-l would not be the major mediator of tbe growth-promoting actions of GH. Perhaps its main roles are the feedback control on GH secretiol1 éUldthe regulation of carbohydrates metabolism by facilitatinginsulin action. Further studies may reveal if lGFALS mutations could be involved in other cases of delay of growth and pubertal development in children. markedly decreases serum IGF-I and IGFBP-3, increases GH secretion, induces insulin resistance, éU1cp1robably causes pubertal del ay with minimal effect on linear growth. Tbese fjndings suggest that total circulating IGF-l would not be the major mediator of tbe growth-promoting actions of GH. Perhaps its main roles are the feedback control on GH secretiol1 éUldthe regulation of carbohydrates metabolism by facilitatinginsulin action. Further studies may reveal if lGFALS mutations could be involved in other cases of delay of growth and pubertal development in children. /lg/ml; -9.7 SDS) were low, éU1dALS was undetectable. An IGF-I generation test and a 6-month GH treatment period were ineffective to induce any changes in IGF-I, IGFBP-3, and ALS levels, as well as to improve growth ve]ocity. Sequencing of the complete coding region of tbe IGFALS gene revealed a homozygous mutation in exon 2 (1338delG; E35fsXI20). This frame-shifLing mutation predicts the formation of a truncaled, most likely inactive protein. Circulating ALS protein was undetectable by westem immunobloting using anLi-ALS antibodies. Incubation of sel1lm with 1251I_GF-l followed by cross-linking and éUlalyzedby size exclusion column chromatography revealed complete inability for temal)´ compJex formation. Oral glucose loads performed before and during GH treatment showed normal glucose ]evels with exaggerated insulin responses, indicatjng some degree of insulin resistance. A 3-month period of metformin treatment reduced basal insulin levels by 47% and insulin sensitivity index improves to 2.1, near to nonnal value. Conclusions: The lack of circulating ALS prevents the formation of the ternary complex, markedly decreases serum IGF-I and IGFBP-3, increases GH secretion, induces insulin resistance, éU1cp1robably causes pubertal del ay with minimal effect on linear growth. Tbese fjndings suggest that total circulating IGF-l would not be the major mediator of tbe growth-promoting actions of GH. Perhaps its main roles are the feedback control on GH secretiol1 éUldthe regulation of carbohydrates metabolism by facilitatinginsulin action. Further studies may reveal if lGFALS mutations could be involved in other cases of delay of growth and pubertal development in children. markedly decreases serum IGF-I and IGFBP-3, increases GH secretion, induces insulin resistance, éU1cp1robably causes pubertal del ay with minimal effect on linear growth. Tbese fjndings suggest that total circulating IGF-l would not be the major mediator of tbe growth-promoting actions of GH. Perhaps its main roles are the feedback control on GH secretiol1 éUldthe regulation of carbohydrates metabolism by facilitatinginsulin action. Further studies may reveal if lGFALS mutations could be involved in other cases of delay of growth and pubertal development in children. chromatography revealed complete inability for temal)´ compJex formation. Oral glucose loads performed before and during GH treatment showed normal glucose ]evels with exaggerated insulin responses, indicatjng some degree of insulin resistance. A 3-month period of metformin treatment reduced basal insulin levels by 47% and insulin sensitivity index improves to 2.1, near to nonnal value. Conclusions: The lack of circulating ALS prevents the formation of the ternary complex, markedly decreases serum IGF-I and IGFBP-3, increases GH secretion, induces insulin resistance, éU1cp1robably causes pubertal del ay with minimal effect on linear growth. Tbese fjndings suggest that total circulating IGF-l would not be the major mediator of tbe growth-promoting actions of GH. Perhaps its main roles are the feedback control on GH secretiol1 éUldthe regulation of carbohydrates metabolism by facilitatinginsulin action. Further studies may reveal if lGFALS mutations could be involved in other cases of delay of growth and pubertal development in children. markedly decreases serum IGF-I and IGFBP-3, increases GH secretion, induces insulin resistance, éU1cp1robably causes pubertal del ay with minimal effect on linear growth. Tbese fjndings suggest that total circulating IGF-l would not be the major mediator of tbe growth-promoting actions of GH. Perhaps its main roles are the feedback control on GH secretiol1 éUldthe regulation of carbohydrates metabolism by facilitatinginsulin action. Further studies may reveal if lGFALS mutations could be involved in other cases of delay of growth and pubertal development in children. by size exclusion column chromatography revealed complete inability for temal)´ compJex formation. Oral glucose loads performed before and during GH treatment showed normal glucose ]evels with exaggerated insulin responses, indicatjng some degree of insulin resistance. A 3-month period of metformin treatment reduced basal insulin levels by 47% and insulin sensitivity index improves to 2.1, near to nonnal value. Conclusions: The lack of circulating ALS prevents the formation of the ternary complex, markedly decreases serum IGF-I and IGFBP-3, increases GH secretion, induces insulin resistance, éU1cp1robably causes pubertal del ay with minimal effect on linear growth. Tbese fjndings suggest that total circulating IGF-l would not be the major mediator of tbe growth-promoting actions of GH. Perhaps its main roles are the feedback control on GH secretiol1 éUldthe regulation of carbohydrates metabolism by facilitatinginsulin action. Further studies may reveal if lGFALS mutations could be involved in other cases of delay of growth and pubertal development in children. markedly decreases serum IGF-I and IGFBP-3, increases GH secretion, induces insulin resistance, éU1cp1robably causes pubertal del ay with minimal effect on linear growth. Tbese fjndings suggest that total circulating IGF-l would not be the major mediator of tbe growth-promoting actions of GH. Perhaps its main roles are the feedback control on GH secretiol1 éUldthe regulation of carbohydrates metabolism by facilitatinginsulin action. Further studies may reveal if lGFALS mutations could be involved in other cases of delay of growth and pubertal development in children. Conclusions: The lack of circulating ALS prevents the formation of the ternary complex, markedly decreases serum IGF-I and IGFBP-3, increases GH secretion, induces insulin resistance, éU1cp1robably causes pubertal del ay with minimal effect on linear growth. Tbese fjndings suggest that total circulating IGF-l would not be the major mediator of tbe growth-promoting actions of GH. Perhaps its main roles are the feedback control on GH secretiol1 éUldthe regulation of carbohydrates metabolism by facilitatinginsulin action. Further studies may reveal if lGFALS mutations could be involved in other cases of delay of growth and pubertal development in children.

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