Greenberg dysplasia is a severe condition characterized by specific bone abnormalities in the developing fetus. This condition is fatal before birth.

The bones of affected individuals do not develop properly, causing a distinctive spotted appearance called moth-eaten bone, which is visible on x-ray images. In addition, the bones have abnormal calcium deposits (ectopic calcification). Affected individuals have extremely short bones in the arms and legs and abnormally flat vertebrae (platyspondyly). Other skeletal abnormalities may include short ribs and extra fingers (polydactyly). In addition, affected fetuses have extensive swelling of the body caused by fluid accumulation (hydrops fetalis). Greenberg dysplasia is also called hydrops-ectopic calcification-moth-eaten skeletal dysplasia (HEM), which reflects the condition's most common features.

Mutations in the LBR gene cause Greenberg dysplasia. This gene provides instructions for making a protein called the lamin B receptor. One region of this protein, called the sterol reductase domain, plays an important role in the production (synthesis) of cholesterol. Cholesterol is a type of fat that is produced in the body and obtained from foods that come from animals: eggs, meat, fish, and dairy products. Cholesterol is necessary for normal embryonic development and has important functions both before and after birth. Cholesterol is an important component of cell membranes and the protective substance covering nerve cells (myelin). Additionally, cholesterol plays a role in the production of certain hormones and digestive acids. During cholesterol synthesis, the sterol reductase function of the lamin B receptor allows the protein to perform one of several steps that convert a molecule called lanosterol to cholesterol.

LBR gene mutations involved in Greenberg dysplasia lead to loss of the sterol reductase function of the lamin B receptor, and research suggests that this loss causes the condition. Absence of the sterol reductase function disrupts the normal synthesis of cholesterol within cells. This absence may also allow potentially toxic byproducts of cholesterol synthesis to build up in the body's tissues. Researchers suspect that low cholesterol levels or an accumulation of other substances disrupts the growth and development of many parts of the body. It is not known, however, how a disturbance of cholesterol synthesis leads to the specific features of Greenberg dysplasia.

Normal Function

The LBR gene provides instructions for making a protein called the lamin B receptor. Different regions (domains) of this protein give it two distinct functions.

One region of the protein, called the sterol reductase domain, gives the protein sterol reductase function (specifically Δ14-sterol reductase function). This function of the lamin B receptor plays an important role in the production (synthesis) of cholesterol. Cholesterol is a lipid (fat) that is obtained from foods that come from animals: eggs, meat, fish, and dairy products. The body also makes (synthesizes) its own cholesterol. During cholesterol synthesis, the sterol reductase function of the lamin B receptor allows the protein to perform one of several chemical reactions that convert a molecule called lanosterol to cholesterol.

The body needs cholesterol to develop and function normally. Before birth, cholesterol interacts with signaling proteins that control early development of the brain, limbs, genitals, and other structures. It is also an important component of cell membranes and myelin, the fatty covering that insulates nerve cells. Additionally, cholesterol is used to make certain hormones and is important for the production of acids used in digestion (bile acids).

Another region of the lamin B receptor, called the DNA-binding domain, attaches (binds) to chromatin, the complex of DNA and proteins that packages DNA into chromosomes. The lamin B receptor can be found in the membrane that surrounds the nucleus (the nuclear envelope). The protein's interaction with chromatin attaches it to the nuclear envelope and helps maintain the chromatin's structure. Proper interaction of chromatin with the nuclear envelope may play a role in several important cellular functions such as making new copies of DNA (replication), controlling the activity of genes, and regulating programmed cell death (apoptosis). The DNA-binding domain of the protein also plays a role in the formation of the nucleus within cells.

Health Conditions Related to Genetic Changes

Greenberg dysplasia

Several mutations in the LBR gene have been found to cause Greenberg dysplasia. This severe condition is characterized by abnormal bone formation and is fatal before birth. Research suggests that this condition is caused by the loss of the sterol reductase function of the lamin B receptor. Some LBR gene mutations that cause Greenberg dysplasia change single protein building blocks (amino acids) in the sterol reductase domain of the lamin B receptor, which leads to the loss of sterol reductase activity. Other mutations lead to an abnormally short protein that is likely nonfunctional.

Loss of the sterol reductase function of the lamin B receptor disrupts the normal synthesis of cholesterol within cells. Absence of this function may also allow potentially toxic byproducts of cholesterol synthesis to build up in the body's tissues. Researchers suspect that low cholesterol levels or an accumulation of other substances disrupts the growth and development of many parts of the body. It is not known, however, how a disturbance of cholesterol synthesis leads to the specific features of Greenberg dysplasia.

Other disorders

Mutations in the LBR gene can also cause Pelger-Huët anomaly, a condition that affects the shape of the nucleus and the structure of chromatin in certain cells but causes no outward signs or symptoms. The nuclei of blood cells called granulocytes normally have multiple segments (or lobes). In contrast, the nuclei of granulocytes in people with Pelger-Huët anomaly have fewer segments than normal (they are hypolobulated). In addition, the chromatin in affected cells appears coarser than usual when viewed under a microscope.

Mutations that cause Pelger-Huët anomaly usually lead to an abnormally short lamin B receptor and reduce the amount of functional protein. It is thought that impairment of the receptor's DNA-binding domain leads to this condition.

Other Names for This Gene

• DHCR14B
• integral nuclear envelope inner membrane protein
• lamin-B receptor
• LBR_HUMAN
• LMN2R
• PHA
• TDRD18

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.