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Normosmic idiopathic hypogonadotropic hypogonadism due to a novel homozygous nonsense c.C969A (p.Y323X) mutation in the KISS1R gene in three unrelated families
Summary Objective The spectrum of genetic alterations in cases of hypogonadotropic hypogonadism continue to expand. However, KISS1R mutations remain rare. The aim of this study was to understand the molecular basis of normosmic idiopathic hypogonadotropic hypogonadism. Methods Clinical characteristi...
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| Published in: | Clinical endocrinology (Oxford) 2015-03, Vol.82 (3), p.429-438 |
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| container_title | Clinical endocrinology (Oxford) |
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| creator | Demirbilek, Huseyin Ozbek, M. Nuri Demir, Korcan Kotan, L. Damla Cesur, Yasar Dogan, Murat Temiz, Fatih Mengen, Eda Gurbuz, Fatih Yuksel, Bilgin Topaloglu, A. Kemal |
| description | Summary
Objective
The spectrum of genetic alterations in cases of hypogonadotropic hypogonadism continue to expand. However, KISS1R mutations remain rare. The aim of this study was to understand the molecular basis of normosmic idiopathic hypogonadotropic hypogonadism.
Methods
Clinical characteristics, hormonal studies and genetic analyses of seven cases with idiopathic normosmic hypogonadotropic hypogonadism (nIHH) from three unrelated consanguineous families are presented.
Results
One male presented with absence of pubertal onset and required surgery for severe penoscrotal hypospadias and cryptorchidism, while other two males had absence of pubertal onset. Two of four female cases required replacement therapy for pubertal onset and maintenance, whereas the other two had spontaneous pubertal onset but incomplete maturation. In sequence analysis, we identified a novel homozygous nonsense (p.Y323X) mutation (c.C969A) in the last exon of the KISS1R gene in all clinically affected cases.
Conclusions
We identified a homozygous nonsense mutation in the KISS1R gene in three unrelated families with nIHH, which enabled us to observe the phenotypic consequences of this rare condition. Escape from nonsense‐mediated decay, and thus production of abnormal proteins, may account for the variable severity of the phenotype. Although KISS1R mutations are extremely rare and can cause a heterogeneous phenotype, analysis of the KISS1R gene should be a part of genetic analysis of patients with nIHH, to allow better understanding of phenotype–genotype relationship of KISS1R mutations and the underlying genetic basis of patients with nIHH. |
| doi_str_mv | 10.1111/cen.12618 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_proquest_miscellaneous_1694969051</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1694969051</sourcerecordid><originalsourceid>FETCH-LOGICAL-i4168-e5e1cf4321871f17fabd45d673e4bcbc59c61372a92e26ec18c76f22a9d59b423</originalsourceid><addsrcrecordid>eNqNUc1u1DAYtBCILoUDL4AscSmHbP0T28mxWnVLoVoE5fdkOc6XXZfETuMEWF6GV8XbLRXihGXJn8czI40HoaeUzGlaxxb8nDJJi3toRrkUGWNS3EczwgnJiJT5AXoU4xUhRBREPUQHTDDJhCxn6NcqDF2InbPY1S70ZtykcbPtwzp4U4dxCP3fgIsdrifAY8AG-_ANWrwJXfi5XYcpJsBHSBvb-aKU5Qk-6udfOOOfX-BuGs3ogsfO43ED-PX55SV9h9fgYQ8NAHjyA7RmhBo3pnOtg_gYPWhMG-HJ7XmIPixP3y9eZhdvzs4XJxeZy6ksMhBAbZNzRgtFG6oaU9W5qKXikFe2sqK0knLFTMmASbC0sEo2LN1rUVY544foaO_bD-F6gjjqzkULbWs8pGSayjJPiYig_0EVilNF1M71-T_UqzANPgXZsQRTrKQ7w2e3rKnqoNb94DozbPWflhLheE_47lrY3r1Tonf161S_vqlfL05XN0NSZHuFiyP8uFOY4atOf6KE_rQ608vlK16oj291yX8DneOwhQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1655272911</pqid></control><display><type>article</type><title>Normosmic idiopathic hypogonadotropic hypogonadism due to a novel homozygous nonsense c.C969A (p.Y323X) mutation in the KISS1R gene in three unrelated families</title><source>Wiley Online Library</source><creator>Demirbilek, Huseyin ; Ozbek, M. Nuri ; Demir, Korcan ; Kotan, L. Damla ; Cesur, Yasar ; Dogan, Murat ; Temiz, Fatih ; Mengen, Eda ; Gurbuz, Fatih ; Yuksel, Bilgin ; Topaloglu, A. Kemal</creator><creatorcontrib>Demirbilek, Huseyin ; Ozbek, M. Nuri ; Demir, Korcan ; Kotan, L. Damla ; Cesur, Yasar ; Dogan, Murat ; Temiz, Fatih ; Mengen, Eda ; Gurbuz, Fatih ; Yuksel, Bilgin ; Topaloglu, A. Kemal</creatorcontrib><description>Summary
Objective
The spectrum of genetic alterations in cases of hypogonadotropic hypogonadism continue to expand. However, KISS1R mutations remain rare. The aim of this study was to understand the molecular basis of normosmic idiopathic hypogonadotropic hypogonadism.
Methods
Clinical characteristics, hormonal studies and genetic analyses of seven cases with idiopathic normosmic hypogonadotropic hypogonadism (nIHH) from three unrelated consanguineous families are presented.
Results
One male presented with absence of pubertal onset and required surgery for severe penoscrotal hypospadias and cryptorchidism, while other two males had absence of pubertal onset. Two of four female cases required replacement therapy for pubertal onset and maintenance, whereas the other two had spontaneous pubertal onset but incomplete maturation. In sequence analysis, we identified a novel homozygous nonsense (p.Y323X) mutation (c.C969A) in the last exon of the KISS1R gene in all clinically affected cases.
Conclusions
We identified a homozygous nonsense mutation in the KISS1R gene in three unrelated families with nIHH, which enabled us to observe the phenotypic consequences of this rare condition. Escape from nonsense‐mediated decay, and thus production of abnormal proteins, may account for the variable severity of the phenotype. Although KISS1R mutations are extremely rare and can cause a heterogeneous phenotype, analysis of the KISS1R gene should be a part of genetic analysis of patients with nIHH, to allow better understanding of phenotype–genotype relationship of KISS1R mutations and the underlying genetic basis of patients with nIHH.</description><identifier>ISSN: 0300-0664</identifier><identifier>EISSN: 1365-2265</identifier><identifier>DOI: 10.1111/cen.12618</identifier><identifier>PMID: 25262569</identifier><language>eng</language><publisher>England: Blackwell Publishing Ltd</publisher><subject>Adolescent ; Adult ; Codon, Nonsense - genetics ; Genotype & phenotype ; Humans ; Hypogonadism - etiology ; Hypogonadism - genetics ; Male ; Medical research ; Mutation ; Receptors, G-Protein-Coupled - genetics ; Receptors, Kisspeptin-1 ; Young Adult</subject><ispartof>Clinical endocrinology (Oxford), 2015-03, Vol.82 (3), p.429-438</ispartof><rights>2014 John Wiley & Sons Ltd</rights><rights>2014 John Wiley & Sons Ltd.</rights><rights>Copyright © 2015 John Wiley & Sons Ltd</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fcen.12618$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fcen.12618$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>315,786,790,27957,27958,50923,51032</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25262569$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Demirbilek, Huseyin</creatorcontrib><creatorcontrib>Ozbek, M. Nuri</creatorcontrib><creatorcontrib>Demir, Korcan</creatorcontrib><creatorcontrib>Kotan, L. Damla</creatorcontrib><creatorcontrib>Cesur, Yasar</creatorcontrib><creatorcontrib>Dogan, Murat</creatorcontrib><creatorcontrib>Temiz, Fatih</creatorcontrib><creatorcontrib>Mengen, Eda</creatorcontrib><creatorcontrib>Gurbuz, Fatih</creatorcontrib><creatorcontrib>Yuksel, Bilgin</creatorcontrib><creatorcontrib>Topaloglu, A. Kemal</creatorcontrib><title>Normosmic idiopathic hypogonadotropic hypogonadism due to a novel homozygous nonsense c.C969A (p.Y323X) mutation in the KISS1R gene in three unrelated families</title><title>Clinical endocrinology (Oxford)</title><addtitle>Clin Endocrinol</addtitle><description>Summary
Objective
The spectrum of genetic alterations in cases of hypogonadotropic hypogonadism continue to expand. However, KISS1R mutations remain rare. The aim of this study was to understand the molecular basis of normosmic idiopathic hypogonadotropic hypogonadism.
Methods
Clinical characteristics, hormonal studies and genetic analyses of seven cases with idiopathic normosmic hypogonadotropic hypogonadism (nIHH) from three unrelated consanguineous families are presented.
Results
One male presented with absence of pubertal onset and required surgery for severe penoscrotal hypospadias and cryptorchidism, while other two males had absence of pubertal onset. Two of four female cases required replacement therapy for pubertal onset and maintenance, whereas the other two had spontaneous pubertal onset but incomplete maturation. In sequence analysis, we identified a novel homozygous nonsense (p.Y323X) mutation (c.C969A) in the last exon of the KISS1R gene in all clinically affected cases.
Conclusions
We identified a homozygous nonsense mutation in the KISS1R gene in three unrelated families with nIHH, which enabled us to observe the phenotypic consequences of this rare condition. Escape from nonsense‐mediated decay, and thus production of abnormal proteins, may account for the variable severity of the phenotype. Although KISS1R mutations are extremely rare and can cause a heterogeneous phenotype, analysis of the KISS1R gene should be a part of genetic analysis of patients with nIHH, to allow better understanding of phenotype–genotype relationship of KISS1R mutations and the underlying genetic basis of patients with nIHH.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Codon, Nonsense - genetics</subject><subject>Genotype & phenotype</subject><subject>Humans</subject><subject>Hypogonadism - etiology</subject><subject>Hypogonadism - genetics</subject><subject>Male</subject><subject>Medical research</subject><subject>Mutation</subject><subject>Receptors, G-Protein-Coupled - genetics</subject><subject>Receptors, Kisspeptin-1</subject><subject>Young Adult</subject><issn>0300-0664</issn><issn>1365-2265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><recordid>eNqNUc1u1DAYtBCILoUDL4AscSmHbP0T28mxWnVLoVoE5fdkOc6XXZfETuMEWF6GV8XbLRXihGXJn8czI40HoaeUzGlaxxb8nDJJi3toRrkUGWNS3EczwgnJiJT5AXoU4xUhRBREPUQHTDDJhCxn6NcqDF2InbPY1S70ZtykcbPtwzp4U4dxCP3fgIsdrifAY8AG-_ANWrwJXfi5XYcpJsBHSBvb-aKU5Qk-6udfOOOfX-BuGs3ogsfO43ED-PX55SV9h9fgYQ8NAHjyA7RmhBo3pnOtg_gYPWhMG-HJ7XmIPixP3y9eZhdvzs4XJxeZy6ksMhBAbZNzRgtFG6oaU9W5qKXikFe2sqK0knLFTMmASbC0sEo2LN1rUVY544foaO_bD-F6gjjqzkULbWs8pGSayjJPiYig_0EVilNF1M71-T_UqzANPgXZsQRTrKQ7w2e3rKnqoNb94DozbPWflhLheE_47lrY3r1Tonf161S_vqlfL05XN0NSZHuFiyP8uFOY4atOf6KE_rQ608vlK16oj291yX8DneOwhQ</recordid><startdate>201503</startdate><enddate>201503</enddate><creator>Demirbilek, Huseyin</creator><creator>Ozbek, M. Nuri</creator><creator>Demir, Korcan</creator><creator>Kotan, L. Damla</creator><creator>Cesur, Yasar</creator><creator>Dogan, Murat</creator><creator>Temiz, Fatih</creator><creator>Mengen, Eda</creator><creator>Gurbuz, Fatih</creator><creator>Yuksel, Bilgin</creator><creator>Topaloglu, A. Kemal</creator><general>Blackwell Publishing Ltd</general><general>Wiley Subscription Services, Inc</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7QP</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>201503</creationdate><title>Normosmic idiopathic hypogonadotropic hypogonadism due to a novel homozygous nonsense c.C969A (p.Y323X) mutation in the KISS1R gene in three unrelated families</title><author>Demirbilek, Huseyin ; Ozbek, M. Nuri ; Demir, Korcan ; Kotan, L. Damla ; Cesur, Yasar ; Dogan, Murat ; Temiz, Fatih ; Mengen, Eda ; Gurbuz, Fatih ; Yuksel, Bilgin ; Topaloglu, A. Kemal</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-i4168-e5e1cf4321871f17fabd45d673e4bcbc59c61372a92e26ec18c76f22a9d59b423</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Codon, Nonsense - genetics</topic><topic>Genotype & phenotype</topic><topic>Humans</topic><topic>Hypogonadism - etiology</topic><topic>Hypogonadism - genetics</topic><topic>Male</topic><topic>Medical research</topic><topic>Mutation</topic><topic>Receptors, G-Protein-Coupled - genetics</topic><topic>Receptors, Kisspeptin-1</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Demirbilek, Huseyin</creatorcontrib><creatorcontrib>Ozbek, M. Nuri</creatorcontrib><creatorcontrib>Demir, Korcan</creatorcontrib><creatorcontrib>Kotan, L. Damla</creatorcontrib><creatorcontrib>Cesur, Yasar</creatorcontrib><creatorcontrib>Dogan, Murat</creatorcontrib><creatorcontrib>Temiz, Fatih</creatorcontrib><creatorcontrib>Mengen, Eda</creatorcontrib><creatorcontrib>Gurbuz, Fatih</creatorcontrib><creatorcontrib>Yuksel, Bilgin</creatorcontrib><creatorcontrib>Topaloglu, A. Kemal</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Clinical endocrinology (Oxford)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Demirbilek, Huseyin</au><au>Ozbek, M. Nuri</au><au>Demir, Korcan</au><au>Kotan, L. Damla</au><au>Cesur, Yasar</au><au>Dogan, Murat</au><au>Temiz, Fatih</au><au>Mengen, Eda</au><au>Gurbuz, Fatih</au><au>Yuksel, Bilgin</au><au>Topaloglu, A. Kemal</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Normosmic idiopathic hypogonadotropic hypogonadism due to a novel homozygous nonsense c.C969A (p.Y323X) mutation in the KISS1R gene in three unrelated families</atitle><jtitle>Clinical endocrinology (Oxford)</jtitle><addtitle>Clin Endocrinol</addtitle><date>2015-03</date><risdate>2015</risdate><volume>82</volume><issue>3</issue><spage>429</spage><epage>438</epage><pages>429-438</pages><issn>0300-0664</issn><eissn>1365-2265</eissn><notes>Turkish Scientific and Technical Research Council (TUBITAK) - No. 1095455</notes><notes>istex:D9888A86D0BA8446A5688EB9C2783E2979C7B171</notes><notes>ArticleID:CEN12618</notes><notes>ark:/67375/WNG-FFJ387VQ-9</notes><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>Summary
Objective
The spectrum of genetic alterations in cases of hypogonadotropic hypogonadism continue to expand. However, KISS1R mutations remain rare. The aim of this study was to understand the molecular basis of normosmic idiopathic hypogonadotropic hypogonadism.
Methods
Clinical characteristics, hormonal studies and genetic analyses of seven cases with idiopathic normosmic hypogonadotropic hypogonadism (nIHH) from three unrelated consanguineous families are presented.
Results
One male presented with absence of pubertal onset and required surgery for severe penoscrotal hypospadias and cryptorchidism, while other two males had absence of pubertal onset. Two of four female cases required replacement therapy for pubertal onset and maintenance, whereas the other two had spontaneous pubertal onset but incomplete maturation. In sequence analysis, we identified a novel homozygous nonsense (p.Y323X) mutation (c.C969A) in the last exon of the KISS1R gene in all clinically affected cases.
Conclusions
We identified a homozygous nonsense mutation in the KISS1R gene in three unrelated families with nIHH, which enabled us to observe the phenotypic consequences of this rare condition. Escape from nonsense‐mediated decay, and thus production of abnormal proteins, may account for the variable severity of the phenotype. Although KISS1R mutations are extremely rare and can cause a heterogeneous phenotype, analysis of the KISS1R gene should be a part of genetic analysis of patients with nIHH, to allow better understanding of phenotype–genotype relationship of KISS1R mutations and the underlying genetic basis of patients with nIHH.</abstract><cop>England</cop><pub>Blackwell Publishing Ltd</pub><pmid>25262569</pmid><doi>10.1111/cen.12618</doi><tpages>10</tpages></addata></record> |
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| ispartof | Clinical endocrinology (Oxford), 2015-03, Vol.82 (3), p.429-438 |
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| subjects | Adolescent Adult Codon, Nonsense - genetics Genotype & phenotype Humans Hypogonadism - etiology Hypogonadism - genetics Male Medical research Mutation Receptors, G-Protein-Coupled - genetics Receptors, Kisspeptin-1 Young Adult |
| title | Normosmic idiopathic hypogonadotropic hypogonadism due to a novel homozygous nonsense c.C969A (p.Y323X) mutation in the KISS1R gene in three unrelated families |
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