Hypogonadism Caused by a Homozygous Missense Mutation in the LHB Gene

by Benjamin Bunting BA(Hons) PGCert

ben bunting BA(Hons) PgCert Sport & Exercise Nutriton  Written by Ben Bunting: BA(Hons), PGCert. Sport & Exercise Nutrition. L2 Strength & Conditioning Coach.


The LHB gene contains homozygous missense mutations in two regions, +1 intron 2 and +1 intron 3. The mutation causes serious splicing disruptions, resulting in an aberrant LHB transcript. The variant is highly conserved from human to cattle.

Types of hypogonadism caused by homozygous missense mutation of the LHB gene

A homozygous missense mutation in the LHB gene can cause different types of hypogonadism. One type is caused by a G-C substitution at position +1 of intron 2, which severely disrupts the splicing of the LHB mRNA. The abnormal splicing produces an aberrant transcript.

The LHB gene is a critical regulator of sperm development. It plays a role in coordinating the production of testosterone, the primary sex steroid hormone. It also controls the synthesis of spermatozoa. Advances in understanding the physiologic principles of male reproduction have made it possible for physicians to identify specific genetic causes of hypogonadism. Fortunately, men with this disorder generally have a good prognosis.

The luteinizing hormone receptor gene is also involved. Mutations in this gene impair the production of the hormone. As a result, the affected men may not be able to conceive or become pregnant.

There is also evidence that the gene is involved in the development of the ovaries. Hypogonadism is caused by a hypogonadism in the ovaries of mice with a S100a4-Cre;Ptch1fl/fl homozygous missense mutation of the LHB gene. Hypogonadism in these mice may be caused by impaired production of testosterone.

Different types of hypogonadism are caused by different mutations in the LHCGR gene. The severe forms cause hypogonadism in men, while mild forms cause hypergonadotropic hypogonadism in women. There have not been any reports of natural inactivating mutations of the LHB gene in animals, although knockout female mice have been produced.

In addition to hypogonadism, LHB-mutated mice have lowered LH levels. In mice with homozygous LHB-Cre mutations, serum FSH and LH levels are significantly lower. Further, homozygous mutant mice have reduced ovarian growth and oocyte degeneration.

Inactivating mutations in the LHB and LHCGR genes are rare in females. However, they give insight into how these genes function in human reproduction. A woman with mutation in the LHB b-subunit gene recently came forward with a phenotype that resembled those caused by LH receptor mutations. Interestingly, mutations in gonadotropin subunit genes are even more rare than those in LH receptor genes.

Inactivating mutations in the LHB gene

The LHB gene is an important component of sperm production. However, it can become inactivated due to certain genetic mutations. For example, G-C substitutions in intron 2 of LHB cause severe splicing defects, resulting in aberrant mRNA transcripts.

Mutations in the LHB gene result in a defect in the production of LH. The result is hypogonadotropic hypogonadism. The disease is rare in women. Women with this disorder have low levels of serum LH, but their pubic hair and breast development is normal. In women, luteinizing hormone replacement therapy can help restore their fertility.

Mutations in the LHB gene have a wide range of clinical consequences. The most severe form causes an ambiguous genitalia, while milder forms cause micropenis and hypergonadotropic hypogonadism. While these mutations are more common in men, women show milder symptoms.

LHB variant highly conserved from human to cattle

Molecular studies of the LHB gene showed that a homozygous missense mutation in exon 3 (c.262C-T) seriously disrupts splicing, resulting in an aberrant transcript. This mutation results in a decrease in LHB mRNA level. The disorder occurs more commonly in men than women.

The LHB gene is responsible for the development of male hypogonadism. A homozygous missense mutation in this gene causes the condition. Men with this disorder must recognize the phenotype even if they have no male family member affected.

In men with this mutation, LH is inactive or has varying immunological activity. Although LH deficiency occurs, sexual differentiation is normal in men with this mutation. LH is required for normal masculinization of the reproductive tract. The mutations in LHB lead to impaired LH secretion and impair puberty.

The LHB gene is a member of the gonadotropin family and is secreted by the adenohypophysis. The hormone has a major role in pubertal development and reproductive function in males. A homozygous missense mutation of the gene causes male hypogonadism. Although the disorder is rare, its diagnosis has been made using next-generation sequencing combined with Sanger sequencing technology.

Although rare in females, homozygous missense mutations in the LHB gene provide insight into the LH receptor's physiological role in human reproduction. Recently, the first woman with a mutation in the LH b-subunit has been reported. Her phenotype is similar to the one of female patients with LH receptor mutations. Mutations in gonadotropin subunit genes are even rarer than mutations in the LH receptor.


One of the causes of male hypogonadism is a homozygous missense mutation in the LHB gene. Affected individuals may exhibit delayed puberty and infertility. Some have no symptoms at all, or their symptoms may be reversible.

An online variant prediction tool suggested that this LHB sequence mutation caused hypogonadism. In addition, the variant had a low allele frequency in the ExAC and gnomAD databases. Sequence alignment analysis also showed that this variant is highly conserved from human to cattle.

A homozygous missense mutation at position +1 in intron 2 of the LHB gene results in a severe disruption in the processing of LHB mRNA. As a result, the mature peptide fails to fold correctly.

This mutation was reported in a patient with hypogonadism caused by selective luteinizing hormone deficiency. The patient, a 28-year-old man from consanguineous parents, underwent Sanger sequencing to confirm the diagnosis. He was treated with hCG therapy to treat his hypogonadism. He is currently on 5000 IU hCG twice-weekly.

The LHCGR gene is a key player in the production of LH in the human reproductive system. A homozygous missense mutation in this gene will result in a feminizing external genitalia. This mutation is associated with a feminizing phenotype, although its effects are more subtle than the disease in men and women.

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