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1. A Genetics-First Approach Revealed Monogenic Disorders in Patients With ARM and VACTERL Anomalies

Author

van de Putte, R. (Romy), Dworschak, G.C. (Gabriel C), Brosens, E. (Erwin), Reutter, H. (Heiko), Marcelis, C.L.M. (Carlo L. M.), Acuna-Hidalgo, R. (Rocio), Kurtas, N.E. (Nehir E.), Steehouwer, M. (Marloes), Dunwoodie, S.L. (Sally L.), Schmiedeke, E. (Eberhard), Märzheuser, S. (Stefanie), Schwarzer, S. (Stefan), Brooks, A.S. (Alice), Klein, A. (Annelies) de, Sloots, C.E.J. (Pim), Tibboel, D. (Dick), Brisighelli, G., Morandi, A. (Anna), Bedeschi, M.F. (Maria F.), Bates, M.D. (Michael D.), Levitt, M.A. (Marc), La Peña, A. (Amparo) de, Blaauw, I. (Ivo) de, Roeleveld, N. (Nel), Brunner, H.G. (Han), Rooij, I.A.L.M. (Iris), Hoischen, A. (Alex), van de Putte, R. (Romy), Dworschak, G.C. (Gabriel C), Brosens, E. (Erwin), Reutter, H. (Heiko), Marcelis, C.L.M. (Carlo L. M.), Acuna-Hidalgo, R. (Rocio), Kurtas, N.E. (Nehir E.), Steehouwer, M. (Marloes), Dunwoodie, S.L. (Sally L.), Schmiedeke, E. (Eberhard), Märzheuser, S. (Stefanie), Schwarzer, S. (Stefan), Brooks, A.S. (Alice), Klein, A. (Annelies) de, Sloots, C.E.J. (Pim), Tibboel, D. (Dick), Brisighelli, G., Morandi, A. (Anna), Bedeschi, M.F. (Maria F.), Bates, M.D. (Michael D.), Levitt, M.A. (Marc), La Peña, A. (Amparo) de, Blaauw, I. (Ivo) de, Roeleveld, N. (Nel), Brunner, H.G. (Han), Rooij, I.A.L.M. (Iris), and Hoischen, A. (Alex)

Abstract

Background: The VATER/VACTERL association (VACTERL) is defined as the non-random occurrence of the following congenital anomalies: Vertebral, Anal, Cardiac, Tracheal-Esophageal, Renal, and Limb anomalies. As no unequivocal candidate gene has been identified yet, patients are diagnosed phenotypically. The aims of this study were to identify patients with monogenic disorders using a genetics-first approach, and to study whether variants in candidate genes are involved in the etiology of VACTERL or the individual features of VACTERL: Anorectal malformation (ARM) or esophageal atresia with or without trachea-esophageal fistula (EA/TEF). Methods: Using molecular inversion probes, a candidate gene panel of 56 genes was sequenced in three patient groups: VACTERL (n = 211), ARM (n = 204), and EA/TEF (n = 95). Loss-of-function (LoF) and additional likely pathogenic missense variants, were prioritized and validated using Sanger sequencing. Validated variants were tested for segregation and patients were clinically re-evaluated. Results: In 7 out of the 510 patients (1.4%), pathogenic or likely pathogenic variants were identified in SALL1, SALL4, and MID1, genes that are associated with Townes-Brocks, Duane-radial-ray, and Opitz-G/BBB syndrome. These syndromes always include ARM or EA/TEF, in combination with at least two other VACTERL features. We did not identify LoF variants in the remaining candidate genes. Conclusions: None of the other candidate genes were identified as novel unequivocal disease genes for VACTERL. However, a genetics-first approach allowed refinement of the clinical diagnosis in seven patients, in whom an alternative molecular-based diagnosis was found with important implications for the counseling of the families.

Published
2020
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2. The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Author

Redin, C. (Claire), Brand, H. (Harrison), Collins, R.L. (Ryan L.), Kammin, T. (Tammy), Mitchell, E. (Elyse), Hodge, J.C. (Jennelle C.), Hanscom, C. (Carrie), Pillalamarri, V. (Vamsee), Seabra, C.M. (Catarina M.), Abbott, M.-A. (Mary-Alice), Abdul-Rahman, O.A. (Omar), Aberg, E. (Erika), Adley, R. (Rhett), Alcaraz-Estrada, S.L. (Sofia L.), Alkuraya, F.S. (Fowzan S), An, Y. (Yu), Anderson, M.-A. (Mary-Anne), Antolik, C. (Caroline), Anyane-Yeboa, K. (Kwame), Atkin, J.F. (Joan), Bartell, T. (Tina), Bernstein, J.A. (Jonathan A.), Beyer, E. (Elizabeth), Blumenthal, I. (Ian), Bongers, E. (Ernie), Brilstra, E.H. (Eva H.), Brown, C.W. (Chester W.), Brüggenwirth, H.T. (Hennie), Callewaert, L., Chiang, C. (Colby), Corning, K. (Ken), Cox, H. (H.), Cuppen, E. (Edwin), Currall, B.B. (Benjamin B.), Cushing, T. (Tom), David, D. (Dezso), Deardorff, M.A. (Matthew), Dheedene, A. (Annelies), D'Hooghe, M. (Marc), Vries, B. (Boukje) de, Earl, D.L. (Dawn L.), Ferguson, H.L. (Heather L.), Fisher, H. (Heather), Fitzpatrick, D.R. (David R.), Gerrol, P. (Pamela), Giachino, D. (Daniela), Glessner, J.T. (Joseph T.), Gliem, T. (Troy), Grady, M. (Margo), Graham, B.H. (Brett H.), Griffis, C. (Cristin), Gripp, K.W. (Karen), Gropman, A.L. (Andrea L.), Hanson-Kahn, A. (Andrea), Harris, D.J. (David J.), Hayden, M.A. (Mark A.), Hill, R. (Rosamund), Hochstenbach, R. (Ron), Hoffman, J.D. (Jodi D.), Hopkin, R., Hubshman, M.W. (Monika W.), Innes, M., Irons, M. (Mira), Irving, M. (Melita), Jacobsen, J.C. (Jessie C.), Janssens, S. (Sandra), Jewett, T. (Tamison), Johnson, J.P. (John P.), Jongmans, M.C.J. (Marjolijn), Kahler, S.G. (Stephen G.), Koolen, D.A. (David), Korzelius, J. (Jerome), Kroisel, P. (Peter), Lacassie, Y. (Yves), Lawless, W. (William), Lemyre, E. (Emmanuelle), Leppig, K. (Kathy), Levin, A.V. (Alex V.), Li, H. (Haibo), Li, H. (Hong), Liao, E.C. (Eric C.), Lim, C. (Cynthia), Lose, E.J. (Edward J.), Lucente, D. (Diane), MacEra, M.J. (Michael J.), Manavalan, P. (Poornima), Mandrile, G. (Giorgia), Marcelis, C.L.M. (Carlo), Margolin, L. (Lauren), Mason, T. (Tamara), Masser-Frye, D. (Diane), McClellan, M.W. (Michael W.), Zepeda Mendoza, C.J. (Cinthya J.), Menten, B., Middelkamp, S. (Sjors), Mikami, L.R. (Liya R.), Moe, E. (Emily), Mohammed, S. (Shabaz), Mononen, T. (Tarja), Mortenson, M.E. (Megan E.), Moya, G. (Graciela), Nieuwint, A.W. (Aggie W.), Ordulu, Z. (Zehra), Parkash, S. (Sandhya), Pauker, S.P. (Susan P.), Pereira, S. (Shahrin), Perrin, D. (Danielle), Phelan, K. (Katy), Piña Aguilar, R.E. (Raul E.), Poddighe, P. (Pino), Pregno, G. (Giulia), Raskin, S. (Salmo), Reis, L. (Linda), Rhead, W. (William), Rita, D. (Debra), Renkens, I. (Ivo), Roelens, F. (Filip), Ruliera, J. (Jayla), Rump, P. (Patrick), Schilit, S.L.P. (Samantha L.P.), Shaheen, R. (Ranad), Sparkes, R. (Rebecca), Spiegel, E. (Erica), Stevens, B. (Blair), Stone, M.R. (Matthew R.), Tagoe, J. (Julia), Thakuria, J.V. (Joseph V.), Bon, B. (Bregje) van, van de Kamp, J.M. (Jiddeke M.), Van Der Burgt, I. (Ineke), Essen, T. (Ton) van, Ravenswaaij-Arts, C.M.A. (Conny) van, Van Roosmalen, M.J. (Markus J.), Vergult, S. (Sarah), Volker-Touw, C.M.L. (Catharina M.L.), Warburton, D. (Dorothy), Waterman, M.J. (Matthew J.), Wiley, S. (Susan), Wilson, A. (Anna), Yerena-De Vega, M.D.L.C.A. (Maria De La Concepcion A), Zori, R.T. (Roberto T.), Levy, B. (Brynn), Brunner, H.G. (Han), Leeuw, N. (Nicole) de, Kloosterman, W.P. (Wigard), Thorland, E.C. (Erik C.), Morton, C.C. (Cynthia), Gusella, J.F. (James), Talkowski, M.E. (Michael E.), Redin, C. (Claire), Brand, H. (Harrison), Collins, R.L. (Ryan L.), Kammin, T. (Tammy), Mitchell, E. (Elyse), Hodge, J.C. (Jennelle C.), Hanscom, C. (Carrie), Pillalamarri, V. (Vamsee), Seabra, C.M. (Catarina M.), Abbott, M.-A. (Mary-Alice), Abdul-Rahman, O.A. (Omar), Aberg, E. (Erika), Adley, R. (Rhett), Alcaraz-Estrada, S.L. (Sofia L.), Alkuraya, F.S. (Fowzan S), An, Y. (Yu), Anderson, M.-A. (Mary-Anne), Antolik, C. (Caroline), Anyane-Yeboa, K. (Kwame), Atkin, J.F. (Joan), Bartell, T. (Tina), Bernstein, J.A. (Jonathan A.), Beyer, E. (Elizabeth), Blumenthal, I. (Ian), Bongers, E. (Ernie), Brilstra, E.H. (Eva H.), Brown, C.W. (Chester W.), Brüggenwirth, H.T. (Hennie), Callewaert, L., Chiang, C. (Colby), Corning, K. (Ken), Cox, H. (H.), Cuppen, E. (Edwin), Currall, B.B. (Benjamin B.), Cushing, T. (Tom), David, D. (Dezso), Deardorff, M.A. (Matthew), Dheedene, A. (Annelies), D'Hooghe, M. (Marc), Vries, B. (Boukje) de, Earl, D.L. (Dawn L.), Ferguson, H.L. (Heather L.), Fisher, H. (Heather), Fitzpatrick, D.R. (David R.), Gerrol, P. (Pamela), Giachino, D. (Daniela), Glessner, J.T. (Joseph T.), Gliem, T. (Troy), Grady, M. (Margo), Graham, B.H. (Brett H.), Griffis, C. (Cristin), Gripp, K.W. (Karen), Gropman, A.L. (Andrea L.), Hanson-Kahn, A. (Andrea), Harris, D.J. (David J.), Hayden, M.A. (Mark A.), Hill, R. (Rosamund), Hochstenbach, R. (Ron), Hoffman, J.D. (Jodi D.), Hopkin, R., Hubshman, M.W. (Monika W.), Innes, M., Irons, M. (Mira), Irving, M. (Melita), Jacobsen, J.C. (Jessie C.), Janssens, S. (Sandra), Jewett, T. (Tamison), Johnson, J.P. (John P.), Jongmans, M.C.J. (Marjolijn), Kahler, S.G. (Stephen G.), Koolen, D.A. (David), Korzelius, J. (Jerome), Kroisel, P. (Peter), Lacassie, Y. (Yves), Lawless, W. (William), Lemyre, E. (Emmanuelle), Leppig, K. (Kathy), Levin, A.V. (Alex V.), Li, H. (Haibo), Li, H. (Hong), Liao, E.C. (Eric C.), Lim, C. (Cynthia), Lose, E.J. (Edward J.), Lucente, D. (Diane), MacEra, M.J. (Michael J.), Manavalan, P. (Poornima), Mandrile, G. (Giorgia), Marcelis, C.L.M. (Carlo), Margolin, L. (Lauren), Mason, T. (Tamara), Masser-Frye, D. (Diane), McClellan, M.W. (Michael W.), Zepeda Mendoza, C.J. (Cinthya J.), Menten, B., Middelkamp, S. (Sjors), Mikami, L.R. (Liya R.), Moe, E. (Emily), Mohammed, S. (Shabaz), Mononen, T. (Tarja), Mortenson, M.E. (Megan E.), Moya, G. (Graciela), Nieuwint, A.W. (Aggie W.), Ordulu, Z. (Zehra), Parkash, S. (Sandhya), Pauker, S.P. (Susan P.), Pereira, S. (Shahrin), Perrin, D. (Danielle), Phelan, K. (Katy), Piña Aguilar, R.E. (Raul E.), Poddighe, P. (Pino), Pregno, G. (Giulia), Raskin, S. (Salmo), Reis, L. (Linda), Rhead, W. (William), Rita, D. (Debra), Renkens, I. (Ivo), Roelens, F. (Filip), Ruliera, J. (Jayla), Rump, P. (Patrick), Schilit, S.L.P. (Samantha L.P.), Shaheen, R. (Ranad), Sparkes, R. (Rebecca), Spiegel, E. (Erica), Stevens, B. (Blair), Stone, M.R. (Matthew R.), Tagoe, J. (Julia), Thakuria, J.V. (Joseph V.), Bon, B. (Bregje) van, van de Kamp, J.M. (Jiddeke M.), Van Der Burgt, I. (Ineke), Essen, T. (Ton) van, Ravenswaaij-Arts, C.M.A. (Conny) van, Van Roosmalen, M.J. (Markus J.), Vergult, S. (Sarah), Volker-Touw, C.M.L. (Catharina M.L.), Warburton, D. (Dorothy), Waterman, M.J. (Matthew J.), Wiley, S. (Susan), Wilson, A. (Anna), Yerena-De Vega, M.D.L.C.A. (Maria De La Concepcion A), Zori, R.T. (Roberto T.), Levy, B. (Brynn), Brunner, H.G. (Han), Leeuw, N. (Nicole) de, Kloosterman, W.P. (Wigard), Thorland, E.C. (Erik C.), Morton, C.C. (Cynthia), Gusella, J.F. (James), and Talkowski, M.E. (Michael E.)

Abstract

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA br

Published
2017
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3. De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations

Author

Reijnders, M.R.F. (Margot R.F.), Zachariadis, V. (Vasilios), Latour, B. (Brooke), Jolly, L. (Lachlan), Mancini, G.M.S. (Grazia), Pfundt, R. (Rolph), Wu, K.M. (Ka Man), Ravenswaaij-Arts, C.M.A. (Conny) van, Veenstra-Knol, H.E. (Hermine), Anderlid, B.-M.M. (Britt-Marie M.), Wood, S.A. (Stephen A.), Cheung, S.W. (Sau Wai), Barnicoat, A. (Angela), Probst, F. (Frank), Magoulas, P. (Pilar), Brooks, A.S. (Alice), Malmgren, H. (Helena), Harila-Saari, A. (Arja), Marcelis, C.M. (Carlo M.), Vreeburg, J.T.M. (Jan), Hobson, E. (Emma), Sutton, V.R. (V. Reid), Stark, Z. (Zornitza), Vogt, J. (Julie), Cooper, N. (Nicola), Lim, J.Y. (Jiin Ying), Price, S. (Susan), Lai, A.H.M. (Angeline Hwei Meeng), Domingo, D. (Deepti), Reversade, B. (Bruno), Gecz, J. (Jozef), Gilissen, C. (Christian), Brunner, H.G. (Han G.), Kini, U. (Usha), Roepman, R. (Ronald), Nordgren, A. (Ann), Kleefstra, T. (Tjitske), Reijnders, M.R.F. (Margot R.F.), Zachariadis, V. (Vasilios), Latour, B. (Brooke), Jolly, L. (Lachlan), Mancini, G.M.S. (Grazia), Pfundt, R. (Rolph), Wu, K.M. (Ka Man), Ravenswaaij-Arts, C.M.A. (Conny) van, Veenstra-Knol, H.E. (Hermine), Anderlid, B.-M.M. (Britt-Marie M.), Wood, S.A. (Stephen A.), Cheung, S.W. (Sau Wai), Barnicoat, A. (Angela), Probst, F. (Frank), Magoulas, P. (Pilar), Brooks, A.S. (Alice), Malmgren, H. (Helena), Harila-Saari, A. (Arja), Marcelis, C.M. (Carlo M.), Vreeburg, J.T.M. (Jan), Hobson, E. (Emma), Sutton, V.R. (V. Reid), Stark, Z. (Zornitza), Vogt, J. (Julie), Cooper, N. (Nicola), Lim, J.Y. (Jiin Ying), Price, S. (Susan), Lai, A.H.M. (Angeline Hwei Meeng), Domingo, D. (Deepti), Reversade, B. (Bruno), Gecz, J. (Jozef), Gilissen, C. (Christian), Brunner, H.G. (Han G.), Kini, U. (Usha), Roepman, R. (Ronald), Nordgren, A. (Ann), and Kleefstra, T. (Tjitske)

Abstract

Mutations in more than a hundred genes have been reported to cause X-linked recessive intellectual disability (ID) mainly in males. In contrast, the number of identified X-linked genes in which de novo mutations specifically cause ID in females is limited. Here, we report 17 females with de novo loss-of-function mutations in USP9X, encoding a highly conserved deubiquitinating enzyme. The females in our study have a specific phenotype that includes ID/developmental delay (DD), characteristic facial features, short stature, and distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial polydactyly, heart defects, hypomastia, cleft palate/bifid uvula, progressive scoliosis, and structural brain abnormalities. Four females from our cohort were identified by targeted genetic testing because their phenotype was suggestive for USP9X mutations. In several females, pigment changes along Blaschko lines and body asymmetry were observed, which is probably related to differential (escape from) X-inactivation between tissues. Expression studies on both mRNA and protein level in affected-female-derived fibroblasts showed significant reduction of USP9X level, confirming the loss-of-function effect of the identified mutations. Given that some features of affected

Published
2016
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4. Mutant luteinizing hormone receptors in a compound heterozygous patient with complete Leydig cell hypoplasia: abnormal processing causes signaling deficiency

Author

Martens, J.W.M. (John), Lumbroso, S., Verhoef-Post, M. (Miriam), Georget, V., Richter-Unruh, A., Szarras-Czapnik, M., Romer, T.E., Brunner, H.G. (Han), Themmen, A.P.N. (Axel), Sultan, Ch., Martens, J.W.M. (John), Lumbroso, S., Verhoef-Post, M. (Miriam), Georget, V., Richter-Unruh, A., Szarras-Czapnik, M., Romer, T.E., Brunner, H.G. (Han), Themmen, A.P.N. (Axel), and Sultan, Ch.

Abstract

Over the past 5 yr several inactivating mutations in the LH receptor gene have been demonstrated to cause Leydig cell hypoplasia, a rare autosomal recessive form of male pseudohermaphroditism. Here, we report the identification of two new LH receptor mutations in a compound heterozygous case of complete Leydig hypoplasia and determine the cause of the signaling deficiency at a molecular level. On the paternal allele of the patient we identified in codon 343 a T to A transversion that changes a conserved cysteine in the hinge region of the receptor to serine (C343S); on the maternal allele a T to C transition causes another conserved cysteine at codon 543 in trans-membrane segment 5 to be altered to arginine (C543R). Both of these mutant receptors are completely devoid of hormone-induced cAMP reporter gene activation. Using Western blotting of expressed LH receptor protein with a hemagglutinin tag, we further show that despite complete absence of total and cell surface hormone binding, protein levels of both mutant LH receptors are only moderately affected.

Published
2002

5. Genotype versus phenotype in families with androgen insensitivity syndrome

Author

Boehmer, A.L.M. (Annemie), Oostdijk, W. (Wilma), Brüggenwirth, H.T. (Hennie), Assendelft, C. van, Drop, S.L.S. (Stenvert), Otten, B.J. (Barto), Verleun-Mooijman, M.C., Niermeijer, M.F. (Martinus), Vroede, M.A. de, Brunner, H.G. (Han), Rouwé, C.W. (Catrienus), Kwast, Th.H. (Theo) van der, Waelkens, J.J.J. (Johan), Kleijer, W.J. (Wim), Boehmer, A.L.M. (Annemie), Oostdijk, W. (Wilma), Brüggenwirth, H.T. (Hennie), Assendelft, C. van, Drop, S.L.S. (Stenvert), Otten, B.J. (Barto), Verleun-Mooijman, M.C., Niermeijer, M.F. (Martinus), Vroede, M.A. de, Brunner, H.G. (Han), Rouwé, C.W. (Catrienus), Kwast, Th.H. (Theo) van der, Waelkens, J.J.J. (Johan), and Kleijer, W.J. (Wim)

Abstract

Androgen insensitivity syndrome encompasses a wide range of phenotypes, which are caused by numerous different mutations in the AR gene. Detailed information on the genotype/phenotype relationship in androgen insensitivity syndrome is important for sex assignment, treatment of androgen insensitivity syndrome patients, genetic counseling of their families, and insight into the functional domains of the AR. The commonly accepted concept of dependence on fetal androgens of the development of Wolffian ducts was studied in complete androgen insensitivity syndrome (CAIS) patients. In a nationwide survey in The Netherlands, all cases (n = 49) with the presumptive diagnosis androgen insensitivity syndrome known to pediatric endocrinologists and clinical geneticists were studied. After studying the clinical phenotype, mutation analysis and functional analysis of mutant receptors were performed using genital skin fibroblasts and in vitro expression studies. Here we report the findings in families with multiple affected cases. Fifty-nine percent of androgen insensitivity syndrome patients had other affected relatives. A total of 17 families were studied, seven families with CAIS (18 patients), nine families with partial androgen insensitivity (24 patients), and one family with female prepubertal phenotypes (two patients). No phenotypic variation was observed in families with CAIS. However, phenotypic variation was observed in one-third of families with partial androgen insensitivity resulting in different sex of rearing and differences in requirement of reconstructive surgery. Intrafamilial phenotypic variation was observed for mutations R846H, M771I, and deletion of amino acid N682. Four newly identified mutations were found. Follow-up in families with different AR gene mutations provided information on residual androgen action in vivo and the development of the prepubertal and adult phenotype. Patients with a functional complete defective AR had some pubic hair, Tanner stage

Published
2001

6. A homozygous mutation in the luteinizing hormone receptor causes partial Leydig cell hypopla phenotype

Author

Martens, J.W.M. (John), Verhoef-Post, M. (Miriam), Abelin, N., Ezabella, M., Toledo, S.P. (Rodrigo), Brunner, H.G. (Han), Themmen, A.P.N. (Axel), Martens, J.W.M. (John), Verhoef-Post, M. (Miriam), Abelin, N., Ezabella, M., Toledo, S.P. (Rodrigo), Brunner, H.G. (Han), and Themmen, A.P.N. (Axel)

Abstract

Leydig cell hypoplasia (LCH) is characterized by a decreased response of the Leydig cells to LH. As a result, patients with this syndrome display aberrant male development ranging from complete pseudohermaphroditism to males with micropenis but with otherwise normal sex characteristics. We have evaluated three brothers with a mild form of LCH. Analysis of their LH receptor (LHR) gene revealed a homozygous missense mutation resulting in a substitution of a lysine residue for a isoleucine residue at position 625 of the receptor. In vitro analysis of this mutant LHR, LHR(I625K), in HEK293 cells indicated that the signaling efficiency was significantly impaired, which explains the partial phenotype. We have compared this mutant LHR to two other mutant LHRs, LHR(A593P) and LHR(S616Y), identified in a complete and partial LCH patient, respectively. Although the ligand-binding affinity for all three mutant receptors was normal, the hormonal response of LHR(A593P) was completely absent and that of LHR(S616Y) and LHR(I625K) was severely impaired. Low cell surface expression explained the reduced response of LHR(S616Y), while for LHR(I625K) this diminished response was due to a combination of low cell surface expression and decreased coupling efficiency. For LHR(A593P), the absence of a reduced response resulted from both poor cell surface expression and a complete deficiency in coupling. Our experiments further show a clear correlation between the severity of the clinical phenotype of patients and overall receptor signal capacity, which is a combination of cell surface expression and coupling efficiency.

Published
1998

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