Polycystic ovary syndrome(PCOS)is a heterogeneous disorder with evidence of polygenetic components,and obesity may be a risk factor for hyperandrogen ism.Previous studies have shown that LHCGR is en riched in the ovar...Polycystic ovary syndrome(PCOS)is a heterogeneous disorder with evidence of polygenetic components,and obesity may be a risk factor for hyperandrogen ism.Previous studies have shown that LHCGR is en riched in the ovary and LHCGR deficiency causes infertility without typical PCOS phenotypes.ALMS1 is implicated in obesity and hyperandrogenism,the common phenotypes among PCOS patients.Through whole-exome sequencing of 22 PCOS families and targeted candidate gene sequencing of additional 65 sporadic PCOS patients,we identified potential causative mutations in LHCGR and ALMS1 in a sibling-pair PCOS family and three sporadic PCOS patients.The expression of LHCGRL638 P in granulosa-like tumor cell line(KGN)cells promoted cyclic adenosine monophosphate production and granulosa cell proliferation,indicating that LHCGRL638 P is an activating mutation.Lhcgr~(L642 P/L642 P)mice showed an irregular estrous cycle,reduced follicles with dynamic folliculogenesis,and increased testosterone(T),estradiol(E2),and dehydroepiandrosterone.Lhcgr~(+/L642 P)AIms1~(+/PB)mice displayed increased T and E2 but decreased late secondary and preovulatory follicles.We showed that activating mutation of LHCGR likely plays important roles in the pathophysiology of PCOS involving abnormal reproductive physiology,whereas ALMS1 deficiency may promote anovulatory infertility via elevated androgens,suggesting that the disturbed LHCGR and ALMS1 cooperatively induce PCOS phenotypes,characterized as anovulation and hyperandrogenemia frequently observed in PCOS patients with obesity.展开更多
BACKGROUND Alström syndrome(AS,OMIM ID 203800)is a rare disease involving multiple organs in children and is mostly reported in non-Chinese patients.In the Chinese population,there are few reports on the clinical...BACKGROUND Alström syndrome(AS,OMIM ID 203800)is a rare disease involving multiple organs in children and is mostly reported in non-Chinese patients.In the Chinese population,there are few reports on the clinical manifestations and pathogenesis of AS.This is the first report on the association between AS and Graves’hyperthyroidism.CASE SUMMARY An 8-year-old Chinese girl was diagnosed with AS.Two years later,Graves’hyperthyroidism developed with progressive liver dysfunction.The patient’s clinical data were collected;DNA from peripheral blood of the proband,parents and sibling was collected for gene mutation detection using the second-generation sequencing method and gene panel for diabetes.The association between the patient’s genotype and clinical phenotype was analyzed.She carried the pathogenic compound heterozygous mutation of ALMS1(c.2296_2299del4 and c.11460C>A).These stop-gain mutations likely caused truncation of the ALMS1 protein.CONCLUSION The manifestation of hyperthyroidism may suggest rapid progression of AS.展开更多
基金jointly supported by the National Key Research and Development Program of China(2018YFC1002104 to L.W.,2018YFC1004904 to B.-L.W.and J.F.,2016YFC1000500 to H.Y.W.and W.F.T.)the National Natural Science Foundation of China([81930036,31521003,31771669]to H.Y.W.)+1 种基金the Commission for Science and Technology of Shanghai Municipality(17JC1400902to H.Y.W.)the MDA-CHB Research Grant to B.-L.W。
文摘Polycystic ovary syndrome(PCOS)is a heterogeneous disorder with evidence of polygenetic components,and obesity may be a risk factor for hyperandrogen ism.Previous studies have shown that LHCGR is en riched in the ovary and LHCGR deficiency causes infertility without typical PCOS phenotypes.ALMS1 is implicated in obesity and hyperandrogenism,the common phenotypes among PCOS patients.Through whole-exome sequencing of 22 PCOS families and targeted candidate gene sequencing of additional 65 sporadic PCOS patients,we identified potential causative mutations in LHCGR and ALMS1 in a sibling-pair PCOS family and three sporadic PCOS patients.The expression of LHCGRL638 P in granulosa-like tumor cell line(KGN)cells promoted cyclic adenosine monophosphate production and granulosa cell proliferation,indicating that LHCGRL638 P is an activating mutation.Lhcgr~(L642 P/L642 P)mice showed an irregular estrous cycle,reduced follicles with dynamic folliculogenesis,and increased testosterone(T),estradiol(E2),and dehydroepiandrosterone.Lhcgr~(+/L642 P)AIms1~(+/PB)mice displayed increased T and E2 but decreased late secondary and preovulatory follicles.We showed that activating mutation of LHCGR likely plays important roles in the pathophysiology of PCOS involving abnormal reproductive physiology,whereas ALMS1 deficiency may promote anovulatory infertility via elevated androgens,suggesting that the disturbed LHCGR and ALMS1 cooperatively induce PCOS phenotypes,characterized as anovulation and hyperandrogenemia frequently observed in PCOS patients with obesity.
文摘BACKGROUND Alström syndrome(AS,OMIM ID 203800)is a rare disease involving multiple organs in children and is mostly reported in non-Chinese patients.In the Chinese population,there are few reports on the clinical manifestations and pathogenesis of AS.This is the first report on the association between AS and Graves’hyperthyroidism.CASE SUMMARY An 8-year-old Chinese girl was diagnosed with AS.Two years later,Graves’hyperthyroidism developed with progressive liver dysfunction.The patient’s clinical data were collected;DNA from peripheral blood of the proband,parents and sibling was collected for gene mutation detection using the second-generation sequencing method and gene panel for diabetes.The association between the patient’s genotype and clinical phenotype was analyzed.She carried the pathogenic compound heterozygous mutation of ALMS1(c.2296_2299del4 and c.11460C>A).These stop-gain mutations likely caused truncation of the ALMS1 protein.CONCLUSION The manifestation of hyperthyroidism may suggest rapid progression of AS.
