Inherited mutation of the luteinizing hormone/choriogonadotropin receptor (LHCGR) in empty follicle syndrome Kemal O. Yariz, Ph.D., Tom Walsh, Ph.D.,

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Inherited mutation of the luteinizing hormone/choriogonadotropin receptor (LHCGR) in empty follicle syndrome Kemal O. Yariz, Ph.D., Tom Walsh, Ph.D., Asli Uzak, M.D., Michail Spiliopoulos, M.D., Duygu Duman, Ph.D., Gogsen Onalan, M.D., Mary-Claire King, Ph.D., Mustafa Tekin, M.D. Fertility and Sterility Volume 96, Issue 2, Pages e125-e130 (August 2011) DOI: 10.1016/j.fertnstert.2011.05.057 Copyright © 2011 American Society for Reproductive Medicine Terms and Conditions

Figure 1 Familial empty follicle syndrome (EFS). (A) Sisters II-8 and II-10 are affected with EFS. Sisters II-4 and II-6 are infertile but did not undertake IVF. LH/choriogonadotropin receptor (LHCGR) genotypes are indicated for enrolled relatives. The affected sisters are homozygous for the mutant allele, and their unaffected sister and both parents are heterozygous carriers. (B) Sequences of the wild-type, heterozygous, and mutant alleles of LHCGR. (C) Conservation of LHCGR: Asparagine at residue 400 is conserved among mammals, birds, and fish. This residue is also highly conserved in the second transmembrane helix of other glycoprotein hormone receptors. Fertility and Sterility 2011 96, e125-e130DOI: (10.1016/j.fertnstert.2011.05.057) Copyright © 2011 American Society for Reproductive Medicine Terms and Conditions

Figure 2 Normal audiologic tests in two sisters previously reported to have sensorineural hearing loss. ABR = auditory brainstem response. Fertility and Sterility 2011 96, e125-e130DOI: (10.1016/j.fertnstert.2011.05.057) Copyright © 2011 American Society for Reproductive Medicine Terms and Conditions

Figure 3 Structure of LHCGR with loss-of-function mutations. (A) A total of 17 loss-of-function missense mutations of LH/choriogonadotropin receptor (LHCGR; blue and purple circles) have been reported to cause Leydig cell hypoplasia and pseudohermaphroditism in males (complete list is available in Table 2). LHCGR p.N400S (red) is the novel mutation associated with empty follicle syndrome in this study. Mutations identified in infertile sisters of affected males in earlier studies are indicated with purple circles. EC = extracellular domain; TM = transmembrane domain (number of TM region is shown under the structure); IC = intracellular domain. The two-dimensional structure of LHCGR was created at the Sequence-Structure-Function Analysis database (22–24). (B) The interaction of Asn400 (red) with Met487 (purple), Trp491 (purple), and Leu452 (green) is critical to maintaining the structural stability of LHCGR (25). A prediction from the structure is that if a smaller serine residue replaces asparagine at residue 400, distances between the side chains of these amino acids would increase, disrupting their interaction. Fertility and Sterility 2011 96, e125-e130DOI: (10.1016/j.fertnstert.2011.05.057) Copyright © 2011 American Society for Reproductive Medicine Terms and Conditions