Aniridia
Paired Box Transcription Factors
WAGR Syndrome
Eye Proteins
Homeodomain Proteins
Repressor Proteins
Iris
Wilms Tumor
Chromosomes, Human, Pair 11
Pedigree
Anterior Eye Segment
Urogenital Abnormalities
Mutational analysis of PAX6: 16 novel mutations including 5 missense mutations with a mild aniridia phenotype. (1/104)
Mutations in the developmental control gene PAX6 have been shown to be the genetic cause of aniridia, which is a severe panocular eye disease characterised by iris hypoplasia. The inheritance is autosomal dominant with high penetrance but variable expressivity. Here we describe a mutational analysis of 27 Danish patients using a dideoxy fingerprinting method, which identified PAX6 mutations in 18 individuals with aniridia. A thorough phenotype description was made for the 18 patients. A total of 19 mutations, of which 16 were novel, are described. Among these were five missense mutations which tended to be associated with a milder aniridia phenotype, and in fact one of them seemed to be non-penetrant. Four of the five missense mutations were located in the paired domain. We also describe a third alternative spliced PAX6 isoform in which two of the four missense mutations would be spliced out. Our observations support the concept of dosage effects of PAX6 mutations as well as presenting evidence for variable expressivity and gonadal mosaicism. (+info)Goniosurgery for prevention of aniridic glaucoma. (2/104)
PURPOSE: We conducted a retrospective study to report the long-term success and complications of modified goniosurgery to prevent aniridic glaucoma, an entity that typically is difficult to control medically or surgically. METHODS: Fifty-five eyes in 33 patients who had aniridia without glaucoma and who had goniosurgery were identified. Ninety-one procedures were performed on 55 eyes by 1 surgeon (D.S.W.). Each eye had an average of 1.65 procedures and an average of 200 degrees of goniosurgery. Average patient age at time of initial goniosurgery was 37 months. There were no operative complications. RESULTS: No eye had a decrease in visual acuity at last follow-up. All eyes had a preoperative intraocular pressure (IOP) of less than 21 mm Hg. At last follow-up (average, 9 years 6 months; range, 8 months to 24 years), 49 eyes (89%) had IOP of less than 22 mm Hg without medications. The remaining 6 eyes (11%) had IOP of less than or equal to 22 mm Hg with up to 2 eye drops. Of 224 aniridic eyes of 112 patients that were seen for eye care by 1 of the authors (D.S.W.), 119 eyes (53%) demonstrated glaucoma, as defined by IOP of greater than 21 mm Hg. CONCLUSIONS: Without prophylactic goniotomy, aniridic glaucoma may be expected in half of patients, and when it occurs, it is extremely difficult to control. Prophylactic goniosurgery in selected eyes of young patients with aniridia is effective in preventing aniridic glaucoma. (+info)The horse homolog of congenital aniridia conforms to codominant inheritance. (3/104)
Anterior segment dysgenesis syndrome occurs frequently in Rocky Mountain horses and has two distinct ocular phenotypes: (1) large cysts originating from the temporal ciliary body or peripheral retina and (2) multiple anterior segment anomalies including ciliary cysts, iris hypoplasia, iridocorneal adhesions and opacification, nuclear cataract, and megalocornea. To determine if anterior segment dysgenesis syndrome is heritable in horses we performed ophthalmic examinations and collected pedigree information on horses (n = 516) in an extended Rocky Mountain horse pedigree. Logistic regressive segregation analysis of a subset of animals (n = 337) in which the ocular phenotypes of progeny and both parents were known indicated that the codominant inheritance model best fit the data. This model predicted cyst phenotype expression in heterozygous animals and multiple anterior segment anomalies in homozygous animals. Several cases of nonpenetrance of the cyst phenotype were detected in one lineage. The close resemblance between the inheritance and lesions observed in Small eye mice and rats, humans with congenital aniridia or anterior segment malformation, and horses with anterior segment dysgenesis syndrome supported the conclusion that anterior segment dysgenesis syndrome in the horse may be homologous to similar ophthalmic anomalies in other species. (+info)3' deletions cause aniridia by preventing PAX6 gene expression. (4/104)
Aniridia is a panocular human eye malformation caused by heterozygous null mutations within PAX6, a paired-box transcription factor, or cytogenetic deletions of chromosome 11p13 that encompass PAX6. Chromosomal rearrangements also have been described that disrupt 11p13 but spare the PAX6 transcription unit in two families with aniridia. These presumably cause a loss of gene expression, by removing positive cis regulatory elements or juxtaposing negative DNA sequences. We report two submicroscopic de novo deletions of 11p13 that cause aniridia but are located >11 kb from the 3' end of PAX6. The clinical manifestations are indistinguishable from cases with chain-terminating mutations in the coding region. Using human x mouse retinoblastoma somatic cell hybrids, we show that PAX6 is transcribed only from the normal allele but not from the deleted chromosome 11 homolog. Our findings suggest that remote 3' regulatory elements are required for initiation of PAX6 expression. (+info)Missense mutation at the C-terminus of PAX6 negatively modulates homeodomain function. (5/104)
PAX6 is essential for ocular morphogenesis. Mutations in the PAX6 gene produce various phenotypes, including aniridia, Peters' anomaly, foveal hypoplasia, autosomal dominant keratitis and congenital cataracts. PAX6 functions as a transcription factor and has two DNA binding domains (a paired domain and a homeodomain) which are joined by a linker, and a transactivation domain enriched in proline, serine and threonine (PST) at the C-terminus. The mechanism of PAX6 function is not clearly understood, and few target genes in vertebrates have been identified. We examined disease-causing missense mutations in the PST domain to understand how they affect the function of PAX6. Upon examining the DNA samples of aniridia patients, we identified three missense mutations in the PST domain: P375Q (a novel mutation) and the previously reported Q422R and X423L mutations. On the basis of functional analysis, the P375Q mutant appears to have a normal transactivation activity but lower DNA binding through the paired domain than the wild-type. The Q422R mutation resulted in the loss of DNA binding ability of the PAX6 homeodomain. Substitution analyses of the C-terminal amino acid (codon 422) indicated that an amino acid at codon 422 is required for DNA binding of the homeodomain of intact PAX6 and that the polarity and charge of the side-chain of the terminal amino acid influence this binding. (+info)Alveolar capillary dysplasia with misalignment of pulmonary veins and anterior segment dysgenesis of the eye: a report of a new association and review of the literature. (6/104)
The association of alveolar capillary dysplasia with misalignment of pulmonary veins (ACD-MPV) and ocular abnormalities has not been previously reported. We present a case of ACD-MPV and anterior segment dysgenesis of the eye in a full-term infant as well as a review of the relevant literature. (+info)Aniridia-associated translocations, DNase hypersensitivity, sequence comparison and transgenic analysis redefine the functional domain of PAX6. (7/104)
The transcription factor PAX6 plays a critical, evolutionarily conserved role in eye, brain and olfactory development. Homozygous loss of PAX6 function affects all expressing tissues and is neonatally lethal; heterozygous null mutations cause aniridia in humans and the Small eye (Sey) phenotype in mice. Several upstream and intragenic PAX6 control elements have been defined, generally through transgenesis. However, aniridia cases with chromosomal rearrangements far downstream of an intact PAX6 gene suggested a requirement for additional cis-acting control for correct gene expression. The likely location of such elements is pinpointed through YAC transgenic studies. A 420 kb yeast artificial chromosome (YAC) clone, extending well beyond the most distant patient breakpoint, was previously shown to rescue homozygous Small eye lethality and correct the heterozygous eye phenotype. We now show that a 310 kb YAC clone, terminating just 5' of the breakpoint, fails to influence the Sey phenotypes. Using evolutionary sequence comparison, DNaseI hypersensitivity analysis and transgenic reporter studies, we have identified a region, >150 kb distal to the major PAX6 promoter P1, containing regulatory elements. Components of this downstream regulatory region drive reporter expression in distinct partial PAX6 patterns, indicating that the functional PAX6 gene domain extends far beyond the transcription unit. (+info)PAX6 mutation as a genetic factor common to aniridia and glucose intolerance. (8/104)
A paired homeodomain transcription factor, PAX6, is a well-known regulator of eye development, and its heterozygous mutations in humans cause congenital eye anomalies such as aniridia. Because it was recently shown that PAX6 also plays an indispensable role in islet cell development, a PAX6 gene mutation in humans may lead to a defect of the endocrine pancreas. Whereas heterozygous mutations in islet-cell transcription factors such as IPF1/IDX-1/STF-1/PDX-1 and NEUROD1/BETA2 serve as a genetic cause of diabetes or glucose intolerance, we investigated the possibility of PAX6 gene mutations being a genetic factor common to aniridia and diabetes. In five aniridia and one Peters' anomaly patients, all of the coding exons and their flanking exon-intron junctions of the PAX6 gene were surveyed for mutations. The results of direct DNA sequencing revealed three different mutations in four aniridia patients: one previously reported type of mutation and two unreported types. In agreement with polypeptide truncation and a lack of the carboxyl-terminal transactivation domain in all of the mutated PAX6 proteins, no transcriptional activity was found in the reporter gene analyses. Oral glucose tolerance tests revealed that all of the patients with a PAX6 gene mutation had glucose intolerance characterized by impaired insulin secretion. Although we did not detect a mutation within the characterized portion of the PAX6 gene in one of the five aniridia patients, diabetes was cosegregated with aniridia in her family, and a single nucleotide polymorphism in intron 9 of the PAX6 gene was correlated with the disorders, suggesting that a mutation, possibly located in an uncharacterized portion of the PAX6 gene, can explain both diabetes and aniridia in this family. In contrast, the patient with Peters' anomaly, for which a PAX6 gene mutation is a relatively rare cause, showed normal glucose tolerance (NGT) and did not show a Pax6 gene mutation. Taken together, our present observations suggest that heterozygous mutations in the PAX6 gene can induce eye anomaly and glucose intolerance in individuals harboring these mutations. (+info)Aniridia is a genetic condition that affects the development of the eye. The most notable feature of aniridia is the partial or complete absence of the colored part of the eye, called the iris. This gives the appearance of a larger than normal pupil and can lead to sensitivity to light (photophobia). Aniridia is usually present at birth and can affect one or both eyes.
The condition is caused by mutations in the PAX6 gene, which plays a crucial role in the early development of the eye. In addition to the iris abnormalities, people with aniridia may also have other eye problems such as cloudy corneas, cataracts, glaucoma, and degeneration of the retina. These complications can lead to decreased vision or blindness if not properly managed.
Aniridia is typically inherited in an autosomal dominant manner, meaning that a child has a 50% chance of inheriting the condition if one parent has it. However, approximately two-thirds of aniridia cases are sporadic, occurring due to new mutations in the PAX6 gene and not inherited from a parent.
It is essential to monitor and manage aniridia-related complications through regular eye examinations and appropriate treatments to preserve vision as much as possible. Some individuals with aniridia may also benefit from low-vision aids, such as magnifiers or telescopic lenses, to help maximize their remaining visual function.
Paired box (PAX) transcription factors are a group of proteins that regulate gene expression during embryonic development and in some adult tissues. They are characterized by the presence of a paired box domain, a conserved DNA-binding motif that recognizes specific DNA sequences. PAX proteins play crucial roles in various developmental processes, such as the formation of the nervous system, eyes, and pancreas. Dysregulation of PAX genes has been implicated in several human diseases, including cancer.
WAGR syndrome is a genetic disorder that stands for four main features: Wilms' tumor (a type of kidney cancer), aniridia (absence of the iris in the eye), genitourinary anomalies, and mental retardation. It is caused by a deletion of genetic material on chromosome 11, which includes the WAFT gene. This syndrome is rare and occurs in approximately 1 in 500,000 individuals.
The Wilms' tumor in WAGR syndrome typically develops during childhood, with about half of affected children developing this type of cancer by age 7. Aniridia is usually present at birth and can cause decreased vision or sensitivity to light. Genitourinary anomalies can include abnormalities of the reproductive and urinary systems, such as undescended testicles in males or structural abnormalities of the kidneys or urinary tract. Mental retardation ranges from mild to severe and is often accompanied by developmental delays and behavioral problems.
Early diagnosis and treatment of WAGR syndrome can improve outcomes for affected individuals. Treatment typically includes surveillance for Wilms' tumor, management of aniridia and genitourinary anomalies, and special education and therapy services for mental retardation.
Eye proteins, also known as ocular proteins, are specific proteins that are found within the eye and play crucial roles in maintaining proper eye function and health. These proteins can be found in various parts of the eye, including the cornea, iris, lens, retina, and other structures. They perform a wide range of functions, such as:
1. Structural support: Proteins like collagen and elastin provide strength and flexibility to the eye's tissues, enabling them to maintain their shape and withstand mechanical stress.
2. Light absorption and transmission: Proteins like opsins and crystallins are involved in capturing and transmitting light signals within the eye, which is essential for vision.
3. Protection against damage: Some eye proteins, such as antioxidant enzymes and heat shock proteins, help protect the eye from oxidative stress, UV radiation, and other environmental factors that can cause damage.
4. Regulation of eye growth and development: Various growth factors and signaling molecules, which are protein-based, contribute to the proper growth, differentiation, and maintenance of eye tissues during embryonic development and throughout adulthood.
5. Immune defense: Proteins involved in the immune response, such as complement components and immunoglobulins, help protect the eye from infection and inflammation.
6. Maintenance of transparency: Crystallin proteins in the lens maintain its transparency, allowing light to pass through unobstructed for clear vision.
7. Neuroprotection: Certain eye proteins, like brain-derived neurotrophic factor (BDNF), support the survival and function of neurons within the retina, helping to preserve vision.
Dysfunction or damage to these eye proteins can contribute to various eye disorders and diseases, such as cataracts, age-related macular degeneration, glaucoma, diabetic retinopathy, and others.
Homeodomain proteins are a group of transcription factors that play crucial roles in the development and differentiation of cells in animals and plants. They are characterized by the presence of a highly conserved DNA-binding domain called the homeodomain, which is typically about 60 amino acids long. The homeodomain consists of three helices, with the third helix responsible for recognizing and binding to specific DNA sequences.
Homeodomain proteins are involved in regulating gene expression during embryonic development, tissue maintenance, and organismal growth. They can act as activators or repressors of transcription, depending on the context and the presence of cofactors. Mutations in homeodomain proteins have been associated with various human diseases, including cancer, congenital abnormalities, and neurological disorders.
Some examples of homeodomain proteins include PAX6, which is essential for eye development, HOX genes, which are involved in body patterning, and NANOG, which plays a role in maintaining pluripotency in stem cells.
Repressor proteins are a type of regulatory protein in molecular biology that suppress the transcription of specific genes into messenger RNA (mRNA) by binding to DNA. They function as part of gene regulation processes, often working in conjunction with an operator region and a promoter region within the DNA molecule. Repressor proteins can be activated or deactivated by various signals, allowing for precise control over gene expression in response to changing cellular conditions.
There are two main types of repressor proteins:
1. DNA-binding repressors: These directly bind to specific DNA sequences (operator regions) near the target gene and prevent RNA polymerase from transcribing the gene into mRNA.
2. Allosteric repressors: These bind to effector molecules, which then cause a conformational change in the repressor protein, enabling it to bind to DNA and inhibit transcription.
Repressor proteins play crucial roles in various biological processes, such as development, metabolism, and stress response, by controlling gene expression patterns in cells.
Eye abnormalities refer to any structural or functional anomalies that affect the eye or its surrounding tissues. These abnormalities can be present at birth (congenital) or acquired later in life due to various factors such as injury, disease, or aging. Some examples of eye abnormalities include:
1. Strabismus: Also known as crossed eyes, strabismus is a condition where the eyes are misaligned and point in different directions.
2. Nystagmus: This is an involuntary movement of the eyes that can be horizontal, vertical, or rotatory.
3. Cataracts: A cataract is a clouding of the lens inside the eye that can cause vision loss.
4. Glaucoma: This is a group of eye conditions that damage the optic nerve and can lead to vision loss.
5. Retinal disorders: These include conditions such as retinal detachment, macular degeneration, and diabetic retinopathy.
6. Corneal abnormalities: These include conditions such as keratoconus, corneal ulcers, and Fuchs' dystrophy.
7. Orbital abnormalities: These include conditions such as orbital tumors, thyroid eye disease, and Graves' ophthalmopathy.
8. Ptosis: This is a condition where the upper eyelid droops over the eye.
9. Color blindness: A condition where a person has difficulty distinguishing between certain colors.
10. Microphthalmia: A condition where one or both eyes are abnormally small.
These are just a few examples of eye abnormalities, and there are many others that can affect the eye and its functioning. If you suspect that you have an eye abnormality, it is important to consult with an ophthalmologist for proper diagnosis and treatment.
In medical terms, the iris refers to the colored portion of the eye that surrounds the pupil. It is a circular structure composed of thin, contractile muscle fibers (radial and circumferential) arranged in a regular pattern. These muscles are controlled by the autonomic nervous system and can adjust the size of the pupil in response to changes in light intensity or emotional arousal. By constricting or dilating the iris, the amount of light entering the eye can be regulated, which helps maintain optimal visual acuity under various lighting conditions.
The color of the iris is determined by the concentration and distribution of melanin pigments within the iris stroma. The iris also contains blood vessels, nerves, and connective tissue that support its structure and function. Anatomically, the iris is continuous with the ciliary body and the choroid, forming part of the uveal tract in the eye.
Wilms tumor, also known as nephroblastoma, is a type of kidney cancer that primarily affects children. It occurs in the cells of the developing kidneys and is named after Dr. Max Wilms, who first described this type of tumor in 1899. Wilms tumor typically develops before the age of 5, with most cases occurring in children under the age of 3.
The medical definition of Wilms tumor is:
A malignant, embryonal kidney tumor originating from the metanephric blastema, which is a mass of undifferentiated cells in the developing kidney. Wilms tumor is characterized by its rapid growth and potential for spread (metastasis) to other parts of the body, particularly the lungs and liver. The tumor usually presents as a large, firm, and irregular mass in the abdomen, and it may be associated with various symptoms such as abdominal pain, swelling, or blood in the urine.
Wilms tumor is typically treated with a combination of surgery, chemotherapy, and radiation therapy. The prognosis for children with Wilms tumor has improved significantly over the past few decades due to advances in treatment methods and early detection.
Human chromosome pair 11 consists of two rod-shaped structures present in the nucleus of each cell in the human body. Each member of the pair is a single chromosome, and together they contain the genetic material that is inherited from both parents. They are located on the eleventh position in the standard karyotype, which is a visual representation of the 23 pairs of human chromosomes.
Chromosome 11 is one of the largest human chromosomes and contains an estimated 135 million base pairs. It contains approximately 1,400 genes that provide instructions for making proteins, as well as many non-coding RNA molecules that play a role in regulating gene expression.
Chromosome 11 is known to contain several important genes and genetic regions associated with various human diseases and conditions. For example, it contains the Wilms' tumor 1 (WT1) gene, which is associated with kidney cancer in children, and the neurofibromatosis type 1 (NF1) gene, which is associated with a genetic disorder that causes benign tumors to grow on nerves throughout the body. Additionally, chromosome 11 contains the region where the ABO blood group genes are located, which determine a person's blood type.
It's worth noting that human chromosomes come in pairs because they contain two copies of each gene, one inherited from the mother and one from the father. This redundancy allows for genetic diversity and provides a backup copy of essential genes, ensuring their proper function and maintaining the stability of the genome.
I must clarify that the term "pedigree" is not typically used in medical definitions. Instead, it is often employed in genetics and breeding, where it refers to the recorded ancestry of an individual or a family, tracing the inheritance of specific traits or diseases. In human genetics, a pedigree can help illustrate the pattern of genetic inheritance in families over multiple generations. However, it is not a medical term with a specific clinical definition.
The anterior eye segment refers to the front portion of the eye, which includes the cornea, iris, ciliary body, and lens. The cornea is the clear, dome-shaped surface at the front of the eye that refracts light entering the eye and provides protection. The iris is the colored part of the eye that controls the amount of light reaching the retina by adjusting the size of the pupil. The ciliary body is a muscle that changes the shape of the lens to focus on objects at different distances. The lens is a transparent structure located behind the iris that further refracts light to provide a clear image. Together, these structures work to focus light onto the retina and enable vision.
Urogenital abnormalities refer to structural or functional anomalies that affect the urinary and genital systems. These two systems are closely linked during embryonic development, and sometimes they may not develop properly, leading to various types of congenital defects. Urogenital abnormalities can range from minor issues like a bifid scrotum (a condition where the scrotum is split into two parts) to more severe problems such as bladder exstrophy (where the bladder develops outside the body).
These conditions may affect urination, reproduction, and sexual function. They can also increase the risk of infections and other complications. Urogenital abnormalities can be diagnosed through physical examination, imaging tests, or genetic testing. Treatment options depend on the specific condition but may include surgery, medication, or lifestyle changes.
Microphthalmos is a medical condition where one or both eyes are abnormally small due to developmental anomalies in the eye. The size of the eye may vary from slightly smaller than normal to barely visible. This condition can occur in isolation or as part of a syndrome with other congenital abnormalities. It can also be associated with other ocular conditions such as cataracts, retinal disorders, and orbital defects. Depending on the severity, microphthalmos may lead to visual impairment or blindness.
Aphakia is a medical condition that refers to the absence of the lens in the eye. This can occur naturally, but it's most commonly the result of surgery to remove a cataract, a cloudy lens that can cause vision loss. In some cases, the lens may not be successfully removed or may be accidentally lost during surgery, leading to aphakia. People with aphakia typically have significant vision problems and may require corrective measures such as glasses, contact lenses, or an intraocular lens implant to improve their vision.