Shao-Ming Wu ¹,Ellen Werber Leschek ²,Owen M. Rennert ³,Wai-Yee Chan ¹

¹ Departments of Pediatrics, Cell Biology, Biochemistry and Molecular Biology, Georgetown University Children's Medical Center, Washington, DC ² Developmental Endocrinology Branch, and ³ Center for Research for Mothers and Children, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD

Table of Contents

1. Abstract

2. Introduction

3. Activating mutations

3.1. Molecular genetics and biochemistry
3.2. Effects on the male
3.3. Effects on the female
3.4. Germline and somatic activating mutations in cancer
3.5. Genotype-phenotype correlation

4. Inactivating mutations

4.1. Molecular genetics and biochemistry
4.2. Effects on the male
4.3. Effects on the female
4.4. Genotype-phenotype correlation

5. Perspective

6. Acknowledgments

7. References

1. Abstract

Human male sexual development is regulated by chorionic gonadotropin (CG) and luteinizing hormone (LH). Aberrant sexual development caused by both activating and inactivating mutations of the human luteinizing hormone receptor (LHR) have been described. All known activating mutations of the LHR are missense mutations caused by single base substitution. The most common activating mutation is the replacement of Asp-578 by Gly due to the substitution of A by G at nucleotide position 1733. All activating mutations are present in exon 11 which encodes the transmembrane domain of the receptor. Constitutive activity of the LHR causes LH releasing hormone-independent precocious puberty in boys and the autosomal dominant disorder familial male-limited precocious puberty (FMPP). Both germline and somatic activating mutations of the LHR have been found in patients with testicular tumors. Activating mutations have no effect on females. The molecular genetics of the inactivating mutations of the LHR are more variable and include single base substitution, partial gene deletion, and insertion. These mutations are not localized and are present in both the extracellular and transmembrane domain of the receptor. Inactivation of the LHR gives rise to the autosomal recessive disorder Leydig cell hypoplasia (LCH) and male hypogonadism or male pseudohermaphroditism. Severity of the clinical phenotype in LCH patients correlates with the amount of residual activity of the mutated receptor. Females are less affected by inactivating mutation of the LHR. Symptoms caused by homozygous inactivating mutation of the LHR include polycystic ovaries and primary amenorrhea.