Shao-Ming Wu

Luteinizing Hormone Receptor Mutations in Disorders of Sexual Development and Cancer

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. A ctivating 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.

POLYMORPHISMS IN THE CODING EXONS OF THE HUMAN LUTEINIZING HORMONE/CHORIONIC GONADOTROPIN RECEPTOR GENE. 637

POLYMORPHISMS IN THE CODING EXONS OF THE HUMAN LUTEINIZING HORMONE/CHORIONIC GONADOTROPIN RECEPTOR GENE. 637

COMPOUND HETEROZYGOUS MUTATIONS OF THE LUTEINIZING HORMONE/CHORIONIC GONADOTROPIN RECEPTOR GENE IN A FAMILY WITH TWO CHILDREN AFFECTED BY LEYDIG CELL HYPOPLASIA (LCH). • 387

COMPOUND HETEROZYGOUS MUTATIONS OF THE LUTEINIZING HORMONE/CHORIONIC GONADOTROPIN RECEPTOR GENE IN A FAMILY WITH TWO CHILDREN AFFECTED BY LEYDIG CELL HYPOPLASIA (LCH). • 387

ALLGROVE (TRIPLE-A) SYNDROME IN PUERTO RICAN KINDREDS MAPS TO CHROMOSOME 12(12q13). † 630

Allgrove syndrome (AS), also known as “triple-A syndrome”, is a rare cause of congenital adrenal insufficiency. It is inherited in an autosomal recessive manner and is associated with achalasia, alacrima and other neurologic defects. The disease was recently linked to chromosome 12q13 in consanguineous families of European ancestry. In the present study, we investigated 4 nonconsanguineous families with documented inheritance of AS for linkage with the reported 12q13 locus. Eighteen subjects were studied; DNA was extracted from peripheral blood and amplified by PCR with primers from polymorphic sequence tagged sites (STSs) located in the chromosome 12q13 region. Two-point logarithm of odds (LOD) score analysis revealed a maximum LOD score of 1.7 for STSs D12S361 and D12S368, without any recombinants[recombination distance (θ) = 0]. Multipoint linkage analysis defined an area of estimated genetic distance less than 0.5cM (approximately 500,000 base-pairs) between STSs D12S368 and D12S96, that is most likely to contain the AS gene(s). We conclude that in Puerto Rican families with AS, this condition maps to the chromosome 12q13 locus, revealing absence of heterogeneity in a genetically distinct population. Candidate genes in the region include those that code for several of the keratin proteins, transcription factors and others.