Uncovering the genetic secrets of fibroids

Uncover the genetic secrets of fibroids. Genetics is the science of studying the genes and mutations of organisms. It is a discipline that studies the structure, function, mutation, transmission and expression of genes. Many fibroid patients want to understand the genetic problems of this disease. So today I will reveal the genetic secrets of fibroids:

NF, also known as multiple neurofibromatosis, is a type of skin syndrome. It is an autosomal dominant genetic disease caused by abnormal development of neural crest cells due to gene defects, resulting in multi-system damage. According to literature reports, the incidence of NF is about 3/100,000 to 5/100,000, and the prevalence is about 1/3000 to 1/3500. According to gene location and clinical manifestations, NF can be divided into NF type I and NF type II. NF type I is the most common in children, accounting for more than 90%, and the gene is located in the 17q11.2 region; NF type II is rare, and the gene is located in the 22q12.2 region. Both are tumor suppressor genes with a penetrance of 100%, but it may not be complete, so the clinical phenotype is diverse. In addition to familial inheritance, half of the patients are caused by sporadic new gene mutations.

At present, there is no effective treatment for NF, mainly genetic counseling and symptomatic treatment. However, as scientists continue to deepen their research on the pathogenesis of genetic molecular biology, achieving genetic and biological targeted treatment is the ultimate goal. The following is a brief introduction to the clinical manifestations of NF and the progress of genetic molecular biological mechanisms.

Clinical manifestations of NF

1. Skin symptoms The skin symptoms of NF are mainly: ① Skin café-au-lait spots are an important sign of NF type I. They exist at birth and can gradually increase in number and size. They are of varying shapes, with unclear and irregular edges and do not protrude from the skin (Figure 1). Before puberty, more than 6 skin café-au-lait spots with a diameter >5 mm (>15 mm after puberty) have a high diagnostic value. Freckles on the body and axillae (Figure 2) are also of diagnostic significance. ② Skin neurofibromas appear in childhood and gradually increase in number. They are mainly distributed on the trunk and limbs. They are mostly pink nodular protrusions, sometimes with peduncles, and the number is uncertain (Figure 3).

2. Neurological symptoms About half of the patients will experience neurological symptoms, which are mainly caused by compression of central or peripheral nerve tumors. The most common tumor of NFⅠ is optic nerve glioma; bilateral acoustic neuroma (Figure 4) is the main feature of NFⅡ, and other spinal cord and peripheral nerve tumors are also common. In children, mental retardation, attention deficit and epileptic seizures may also occur.

3. Ocular symptoms: Small miliary brown nodules with clear borders can be seen on the iris under slit lamp. These are iris hamartomas, also known as Lisch nodules. They may gradually increase with age and can be seen in all patients after puberty. They are unique to NFⅠ type. Optic nerve gliomas can cause exophthalmos and vision loss.

4. Other common congenital developmental abnormalities of the skeletal system include congenital skeletal dysplasia, scoliosis, kyphosis, thinning of the bone cortex, pathological fractures and tibial pseudoarthrosis.

Tumors can occur in the mediastinum and other areas.

NFⅠ gene and pathogenic biological mechanism

The NF1 type gene is located in the 17q11.2 region and consists of 60 exons and introns, encoding neurofibromin. The main functional region of neurofibromin (encoded by exons 20 to 27) has obvious sequence homology with the gene product of the catalytic region of mammalian guanosine triphosphate activated protein (GAP), and this region is called the NF1GAP-related region (GRD).

GRD can activate Ras2GTPase in vivo, allowing the active guanosine triphosphate (GTP) of ras protein to bind

The form of GRD is converted into an inactive guanosine diphosphate (GDP) binding form, which inhibits the AMP signal transduction pathway of the Ras cycle, thereby inhibiting the growth of tumor cells. Therefore, GRD is a negative regulator of Ras signal transduction and is the key to the NF1 gene inhibiting tumorigenesis. At the same time, Ras signal transduction may also inhibit tumorigenesis through the mTOR pathway (which participates in cell differentiation and proliferation and plays a key role in the pathogenesis of another neurocutaneous syndrome, tuberous sclerosis).

Upstream of GRD, a cysteine/serine-rich region (CSRD) may be involved in the positive regulation of intracellular cyclic adenosine monophosphate (cAMP) levels and the regulation of cAMP-dependent protein kinase A (PKA) signaling pathways, thereby participating in the regulation of neuronal cell growth and differentiation. Its regulation and dysfunction may lead to learning, memory and intellectual development disorders.

The spontaneous mutation rate of NFⅠ gene is high, and 50% of patients have new mutations. It is one of the gene sites with the highest mutation rate in human genes. However, no clear mutation hotspots have been found in the study, and there is no obvious connection between its genotype and phenotype. Mutations run through the entire NF1 gene sequence, including chromosome aberrations, base substitutions, insertion mutations, deletion mutations, duplication mutations, nonsense mutations, missense mutations, termination mutations, 3' untranslated region mutations, etc., and mutations are relatively concentrated in exons 21-27 and 11-17.

In sporadic cases, 90 percent of new mutations occur on chromosomes of paternal origin, with base substitution mutations more common in paternal cells and deletions more common in maternal cells.

NFⅡ gene and pathogenic biological mechanism

The NFⅡ gene is located in the 22q12.2 region and contains a total of 17 exons, of which only the first 15 exons have pathogenic mutations, and exons 16 and 17 are optional splicing exons. The gene encoding product is called merlin, which consists of a FERM region, an α-helical region, and a C-terminus. There are two subtypes of merlin in the human body, type I and type II, but only merlin type I has tumor suppressor activity. After dephosphorylation of serine at position 518 of merlin, a closed active state is formed. Its upstream P21 activated kinase (PAK), cAMP-dependent protein kinase A, and myosin phosphatase 1 protein phosphatase 1δ jointly regulate the tumor suppressor activity of merlin by regulating the phosphorylation of merlin.

Merlin is concentrated on the surface of cell membrane and cell scaffold, and may affect cell proliferation and differentiation by indirectly regulating cell membrane proteins [such as CD44, epidermal growth factor receptor (EGFR), etc.], cell adhesion factors (such as β-catenin, E-cadherin, etc.) and cytoskeleton (such as βⅡ membrane contractile protein, F-actin, etc.) or interacting with cytoplasmic proteins [such as phosphatidylinositol 3-kinase (PIKE-L), eukaryotic initiation factor 3 (eiF3c), etc.] to regulate various downstream mitogenic signaling pathways (such as PI3K, MAPK).

NFⅡ mutations can be roughly divided into two categories: germ cell mutations and somatic mutations. Most typical NFⅡ patients are caused by germ cell NF2 gene mutations. Mutations include small fragment deletions or insertions, allele loss, nonsense mutations, missense mutations, frameshift mutations, splicing mutations, and mosaic mutations. Usually, missense mutations and large fragment deletions have mild clinical manifestations, while nonsense mutations or frameshift mutations have more severe clinical manifestations.

At present, NF treatment is limited to tumor surgery and symptomatic treatment, but with the development of molecular biology, molecular genetics and other disciplines, the molecular pathogenesis and genetic research of NF will continue to deepen, thus providing greater help for genetic counseling, early prenatal diagnosis, and even clinical etiology treatment.