Dyskeratosis congenita
Encyclopedia
Dyskeratosis congenita also called Zinsser-Cole-Engman syndrome, is a rare progressive congenital disorder
which results in what in some ways resembles premature aging (similar to progeria
). The disease mainly affects the integumentary system
with a major consequence being anomalies of the bone marrow
.
of the nail
s, leukoplakia
of the oral mucosa, continuous lacrimation due to atresia
of the lacrimal ducts, often thrombocytopenia
, anemia
, testicular atrophy
in the male carriers, and predisposition to cancer
. Many of these symptoms are characteristic of geriatrics
, and those carrying the more serious forms of the disease often have significantly shortened lifespans.
Clinical Feature
Age
The mucocutaneous features of DKC typically develop between ages 5 and 15 years. The median age of onset of the peripheral cytopenia is 10 years.
Sex
The male-to-female ratio is approximately 3:1.
Physical
The triad of reticulated hyperpigmentation of the skin, nail dystrophy, and leukoplakia characterizes DKC. The syndrome is clinically heterogeneous; in addition to the diagnostic mucocutaneous features and bone marrow failure, affected individuals can have a variety of other clinical features.
Cutaneous findings
The primary finding is abnormal skin pigmentation, with tan-to-gray hyperpigmented or hypopigmented macules and patches in a mottled or reticulated pattern. Reticulated pigmentation occurs in approximately 90% of patients. Poikilodermatous changes with atrophy and telangiectasia are common.
The cutaneous presentation may clinically and histologically resemble graft versus host disease. The typical distribution involves the sun-exposed areas, including the upper trunk, neck, and face.
Other cutaneous findings may include alopecia of the scalp, eyebrows, and eyelashes; premature graying of the hair; hyperhidrosis; hyperkeratosis of the palms and soles; and adermatoglyphia (loss of dermal ridges on fingers and toes).
Nail findings
Nail dystrophy is seen in approximately 90% of patients, with fingernail involvement often preceding toenail involvement.
Progressive nail dystrophy begins with ridging and longitudinal splitting. Progressive atrophy, thinning, pterygium, and distortion eventuate in small, rudimentary, or absent nails.
Mucosal findings
Mucosal leukoplakia occurs in approximately 80% of patients and typically involves the buccal mucosa, tongue, and oropharynx. The leukoplakia may become verrucous, and ulceration may occur. Patients also may have an increased prevalence and severity of periodontal disease.
Other mucosal sites may be involved (e.g., esophagus, urethral meatus, glans penis, lacrimal duct, conjunctiva, vagina, anus). Constriction and stenosis can occur at these sites, with subsequent development of dysphagia, dysuria, phimosis, and epiphora.
Bone marrow failure
Approximately 90% have peripheral cytopenia of one or more lineages. In some cases, this is the initial presentation, with a median age of onset of 10 years.
Bone marrow failure is a major cause of death, with approximately 70% of deaths related to bleeding and opportunistic infections as a result of bone marrow failure.
Pulmonary complications
Approximately 20% of individuals with DKC develop pulmonary complications, including pulmonary fibrosis and abnormalities of pulmonary vasculature.
The recommendation is that DKC patients avoid taking drugs with pulmonary toxicity (e.g., busulfan) and that they have their lungs shielded from radiation during BMT.
Increased risk of malignancy
Patients have an increased prevalence of malignant mucosal neoplasms, particularly squamous cell carcinoma of the mouth, nasopharynx, esophagus, rectum, vagina, or cervix. These often occur within sites of leukoplakia.
The prevalence of squamous cell carcinoma of the skin is also increased. Other malignancies reported include Hodgkin lymphoma, adenocarcinoma of the gastrointestinal tract, and bronchial and laryngeal carcinoma.
Malignancy tends to develop in the third decade of life.
Neurologic system findings: Patients may have learning difficulties and mental retardation.
Ophthalmic system findings : DKC reportedly is associated with conjunctivitis, blepharitides, and pterygium. Lacrimal duct stenosis resulting in epiphora (i.e., excessive tearing) occurs in approximately 80% of patients.
Skeletal system findings: Patients may have mandibular hypoplasia, osteoporosis, avascular necrosis, and scoliosis.
Gastrointestinal system findings: These may include esophageal webs, hepatosplenomegaly, and cirrhosis.
Genitourinary system findings:: Hypospastic testes, hypospadias, and ureteral stenosis are reported.
Female carriers: Female carries of DKC may have subtle clinical features. One study showed that 3 of 20 female carriers had clinical features that included a single dystrophic nail, a patch of hypopigmentation, or mild leukoplakia.
maintenance. Specifically, the disease is related to one or more mutations which directly or indirectly affect the vertebrate
telomerase
RNA component (TERC).
Telomerase is a reverse transcriptase
which maintains a specific repeat sequence of DNA
, the telomere, during development. Telomeres are placed by telomerase on both ends of linear chromosomes as a way to protect linear DNA from general forms of chemical damage and to correct for the chromosomal end-shortening that occurs during normal DNA replication
. This end-shortening is the result of the eukaryotic DNA polymerase
s having no mechanism for synthesizing the final nucleotide
s present on the end of the “lagging strand” of double stranded DNA. DNA polymerase can only synthesize new DNA from an old DNA strand in the 5'->3' direction. Given that DNA has two strands that are complementary, one strand must be 5'->3' while the other is 3'->5'. This inability to synthesize in the 3'->5' directionality is compensated with the use of Okazaki fragment
s, short pieces of DNA that are synthesized 5'->3' from the 3'->5' as the replication fork moves. As DNA polymerase requires RNA primers
for DNA binding in order to commence replication, each Okazaki fragment is thus preceded by an RNA primer on the strand being synthesized. When the end of the chromosome is reached, the final RNA primer is placed upon this nucleotide region, and it is inevitably removed. Unfortunately once the primer is removed, DNA polymerase is unable to synthesize the remaining bases.
Sufferers of DKC have been shown to have a reduction in TERC levels invariably affecting the normal function of telomerase which maintains these telomeres. With TERC levels down, telomere maintenance during development suffers accordingly. In humans, telomerase is inactive following the stages early development (except in extreme cases such as cancer). Thus, if telomerase is not able to efficiently affect the DNA in the beginning of life, chromosomal instability becomes a grave possibility in individuals much earlier than would be expected.
A study shows that proliferative defects in DC skin keratinocytes are corrected by expression of the telomerase reverse transcriptase
, TERT, or by activation of endogenous telomerase through expression of papillomavirus E6/E7 or the telomerase RNA
component, TERC. Experimental Dermatology 2010; 19: 279–288
ian H/ACA ribonucleoprotein
contains four protein
subunits: dyskerin, Gar1, Nop10, and Nhp2. Mutation
s in Nop10, Nhp2 and dyskerin1 have all been shown to lead to DKC-like symptoms.
of DKC individuals may depend upon which protein has incurred a mutation. One documented autosomal recessive mutation in a family that carries DKC has been found in Nop10. Specifically, the mutation is a change of base from cytosine to thymine in a highly conserved region of the Nop10 sequence. This mutation, on chromosome 15
, results in an amino acid
change from arginine
to tryptophan
. Homozygous recessive individuals show the symptoms of dyskeratosis congenita in full. As compared to age-matched normal individuals, those suffering from DKC have telomeres of a much shorter length. Furthermore, heterozygotes, those who have one normal allele
and one coding for the disease, also show relatively shortened telomeres. The cause of this was determined to be a reduction in TERC levels in those with the Nop10 mutation. With TERC levels down, telomere maintenance, especially in development, would be presumed to suffer accordingly. This would lead to the telomere shortening described.
Nhp2 mutations are similar in characterization to Nop10. These mutations are also autosomal recessive with three specific single-nucleotide polymorphisms being recognized which result in dyskeratosis congenita. Also like Nop10, individuals with these Nhp2 mutations have a reduction in the amount of telomerase RNA component (TERC) present in the cell. Again it can be presumed that a reduction in TERC results in aberrant telomere maintenance and thus shortened telomeres. Those homozygous recessive for mutations in Nhp2 do show shorter telomeres when compared with age-matched normal individuals.
in the gene DKC1. This results in the X-linked recessive form of the disease wherein the major protein affected is dyskerin. Of the five mutations described by Heiss and colleagues in Nature Genetics, four were single nucleotide polymorphisms all resulting in the change of highly conserved amino acids
. One case was an in-frame deletion resulting in the loss of a leucine
residue
, also conserved in mammals. In three of the cases, the specific amino acids affected (phenylalanine
, proline
, glycine
) are found in the same locus
in humans as they are in brewers yeast (S. Cerevisiae) and the brown rat
(R. Norvegicus). This establishes the sequence conservation and importance of dyskerin within the eukaryotes. The relevant nature of dyskerin throughout most species is to catalyze the post-transcriptional pseudouridylation
of specific uridine
s found in non-coding RNAs, such as ribosomal RNA
(rRNA). Cbf5, the yeast analog of human dyskerin, is indeed known to be associated with the processing and maturation of rRNA. In humans this role can be attributed to dyskerin. Thus, the X-linked form of this disease may result in specific issues related to dysfunctional rRNA and perhaps a graver phenotype. Within the vertebrates, as opposed to single celled eukaryotes, dyskerin is a key component of the telomerase RNA component (TERC) in the form of the H/ACA motif. This X-linked variety, like the Nop10 and Nhp2 mutations, demonstrates shortened telomeres as a result of lower TERC concentrations.
which includes 74 bases coding for a section of the H/ACA domain. These three different mutations result in a mild form of dyskeratosis congenita which uniquely follows an autosomal dominant pattern of inheritance. Premature graying, early dental loss, predisposition to skin cancer, as well as shortening of telomere length continue to be characteristic of this disease.
ical nature of cancer predisposition in individuals who seem to lack one of the required components for cancerous lesions. It is discussed that with reduced telomeres, chromosomes will likely be attached together at their ends through the non-homologous end joining
pathway (NHEJ). If this were a common enough occurrence, malignancy even without functional telomerase seems probable.
Congenital disorder
A congenital disorder, or congenital disease, is a condition existing at birth and often before birth, or that develops during the first month of life , regardless of causation...
which results in what in some ways resembles premature aging (similar to progeria
Progeria
Progeria is an extremely rare genetic condition wherein symptoms resembling aspects of aging are manifested at an early age. The word progeria comes from the Greek words "pro" , meaning "before", and "géras" , meaning "old age"...
). The disease mainly affects the integumentary system
Integumentary system
The integumentary system is the organ system that protects the body from damage, comprising the skin and its appendages...
with a major consequence being anomalies of the bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
.
Characteristics
DKC can be characterized by cutaneous pigmentation, premature graying, dystrophyDystrophy
Dystrophy is any condition of abnormal development, often denoting the degeneration of muscles.-Types:* Muscular dystrophy* Duchenne muscular dystrophy* Becker's muscular dystrophy* Reflex neurovascular dystrophy* Retinal dystrophy* Conal dystrophy...
of the nail
Nail (anatomy)
A nail is a horn-like envelope covering the dorsal aspect of the terminal phalanges of fingers and toes in humans, most non-human primates, and a few other mammals. Nails are similar to claws, which are found on numerous other animals....
s, leukoplakia
Leukoplakia
Leukoplakia is a clinical term used to describe patches of keratosis. It is visible as adherent white patches on the mucous membranes of the oral cavity, including the tongue, but also other areas of the gastro-intestinal tract, urinary tract and the genitals. The clinical appearance is highly...
of the oral mucosa, continuous lacrimation due to atresia
Atresia
Atresia is a condition in which a body orifice or passage in the body is abnormally closed or absent.Examples of atresia include:* Imperforate anus - malformation of the opening between the rectum and anus....
of the lacrimal ducts, often thrombocytopenia
Thrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
, anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
, testicular atrophy
Testicular atrophy
Testicular atrophy is a medical condition in which the male reproductive organs diminish in size and may be accompanied by loss of function. This does not refer to temporary changes, such as those brought on by cold.Some medications can cause testicular atrophy...
in the male carriers, and predisposition to cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
. Many of these symptoms are characteristic of geriatrics
Geriatrics
Geriatrics is a sub-specialty of internal medicine and family medicine that focuses on health care of elderly people. It aims to promote health by preventing and treating diseases and disabilities in older adults. There is no set age at which patients may be under the care of a geriatrician, or...
, and those carrying the more serious forms of the disease often have significantly shortened lifespans.
Clinical Feature
Age
The mucocutaneous features of DKC typically develop between ages 5 and 15 years. The median age of onset of the peripheral cytopenia is 10 years.
Sex
The male-to-female ratio is approximately 3:1.
Physical
The triad of reticulated hyperpigmentation of the skin, nail dystrophy, and leukoplakia characterizes DKC. The syndrome is clinically heterogeneous; in addition to the diagnostic mucocutaneous features and bone marrow failure, affected individuals can have a variety of other clinical features.
Cutaneous findings
The primary finding is abnormal skin pigmentation, with tan-to-gray hyperpigmented or hypopigmented macules and patches in a mottled or reticulated pattern. Reticulated pigmentation occurs in approximately 90% of patients. Poikilodermatous changes with atrophy and telangiectasia are common.
The cutaneous presentation may clinically and histologically resemble graft versus host disease. The typical distribution involves the sun-exposed areas, including the upper trunk, neck, and face.
Other cutaneous findings may include alopecia of the scalp, eyebrows, and eyelashes; premature graying of the hair; hyperhidrosis; hyperkeratosis of the palms and soles; and adermatoglyphia (loss of dermal ridges on fingers and toes).
Nail findings
Nail dystrophy is seen in approximately 90% of patients, with fingernail involvement often preceding toenail involvement.
Progressive nail dystrophy begins with ridging and longitudinal splitting. Progressive atrophy, thinning, pterygium, and distortion eventuate in small, rudimentary, or absent nails.
Mucosal findings
Mucosal leukoplakia occurs in approximately 80% of patients and typically involves the buccal mucosa, tongue, and oropharynx. The leukoplakia may become verrucous, and ulceration may occur. Patients also may have an increased prevalence and severity of periodontal disease.
Other mucosal sites may be involved (e.g., esophagus, urethral meatus, glans penis, lacrimal duct, conjunctiva, vagina, anus). Constriction and stenosis can occur at these sites, with subsequent development of dysphagia, dysuria, phimosis, and epiphora.
Bone marrow failure
Approximately 90% have peripheral cytopenia of one or more lineages. In some cases, this is the initial presentation, with a median age of onset of 10 years.
Bone marrow failure is a major cause of death, with approximately 70% of deaths related to bleeding and opportunistic infections as a result of bone marrow failure.
Pulmonary complications
Approximately 20% of individuals with DKC develop pulmonary complications, including pulmonary fibrosis and abnormalities of pulmonary vasculature.
The recommendation is that DKC patients avoid taking drugs with pulmonary toxicity (e.g., busulfan) and that they have their lungs shielded from radiation during BMT.
Increased risk of malignancy
Patients have an increased prevalence of malignant mucosal neoplasms, particularly squamous cell carcinoma of the mouth, nasopharynx, esophagus, rectum, vagina, or cervix. These often occur within sites of leukoplakia.
The prevalence of squamous cell carcinoma of the skin is also increased. Other malignancies reported include Hodgkin lymphoma, adenocarcinoma of the gastrointestinal tract, and bronchial and laryngeal carcinoma.
Malignancy tends to develop in the third decade of life.
Neurologic system findings: Patients may have learning difficulties and mental retardation.
Ophthalmic system findings : DKC reportedly is associated with conjunctivitis, blepharitides, and pterygium. Lacrimal duct stenosis resulting in epiphora (i.e., excessive tearing) occurs in approximately 80% of patients.
Skeletal system findings: Patients may have mandibular hypoplasia, osteoporosis, avascular necrosis, and scoliosis.
Gastrointestinal system findings: These may include esophageal webs, hepatosplenomegaly, and cirrhosis.
Genitourinary system findings:: Hypospastic testes, hypospadias, and ureteral stenosis are reported.
Female carriers: Female carries of DKC may have subtle clinical features. One study showed that 3 of 20 female carriers had clinical features that included a single dystrophic nail, a patch of hypopigmentation, or mild leukoplakia.
Pathophysiology
Though the exact pathology of the disease is not yet fully understood, most evidence points to dyskeratosis congenita being primarily a disorder of poor telomereTelomere
A telomere is a region of repetitive DNA sequences at the end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. Its name is derived from the Greek nouns telos "end" and merοs "part"...
maintenance. Specifically, the disease is related to one or more mutations which directly or indirectly affect the vertebrate
Vertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...
telomerase
Telomerase
Telomerase is an enzyme that adds DNA sequence repeats to the 3' end of DNA strands in the telomere regions, which are found at the ends of eukaryotic chromosomes. This region of repeated nucleotide called telomeres contains non-coding DNA material and prevents constant loss of important DNA from...
RNA component (TERC).
Telomerase is a reverse transcriptase
Reverse transcriptase
In the fields of molecular biology and biochemistry, a reverse transcriptase, also known as RNA-dependent DNA polymerase, is a DNA polymerase enzyme that transcribes single-stranded RNA into single-stranded DNA. It also helps in the formation of a double helix DNA once the RNA has been reverse...
which maintains a specific repeat sequence of DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
, the telomere, during development. Telomeres are placed by telomerase on both ends of linear chromosomes as a way to protect linear DNA from general forms of chemical damage and to correct for the chromosomal end-shortening that occurs during normal DNA replication
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
. This end-shortening is the result of the eukaryotic DNA polymerase
DNA polymerase
A DNA polymerase is an enzyme that helps catalyze in the polymerization of deoxyribonucleotides into a DNA strand. DNA polymerases are best known for their feedback role in DNA replication, in which the polymerase "reads" an intact DNA strand as a template and uses it to synthesize the new strand....
s having no mechanism for synthesizing the final nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
s present on the end of the “lagging strand” of double stranded DNA. DNA polymerase can only synthesize new DNA from an old DNA strand in the 5'->3' direction. Given that DNA has two strands that are complementary, one strand must be 5'->3' while the other is 3'->5'. This inability to synthesize in the 3'->5' directionality is compensated with the use of Okazaki fragment
Okazaki fragment
Okazaki fragments are short molecules of single-stranded DNA that are formed on the lagging strand during DNA replication. They are between 1,000 to 2,000 nucleotides long in Escherichia coli and are between 100 to 200 nucleotides long in eukaryotes....
s, short pieces of DNA that are synthesized 5'->3' from the 3'->5' as the replication fork moves. As DNA polymerase requires RNA primers
Primer (molecular biology)
A primer is a strand of nucleic acid that serves as a starting point for DNA synthesis. They are required for DNA replication because the enzymes that catalyze this process, DNA polymerases, can only add new nucleotides to an existing strand of DNA...
for DNA binding in order to commence replication, each Okazaki fragment is thus preceded by an RNA primer on the strand being synthesized. When the end of the chromosome is reached, the final RNA primer is placed upon this nucleotide region, and it is inevitably removed. Unfortunately once the primer is removed, DNA polymerase is unable to synthesize the remaining bases.
Sufferers of DKC have been shown to have a reduction in TERC levels invariably affecting the normal function of telomerase which maintains these telomeres. With TERC levels down, telomere maintenance during development suffers accordingly. In humans, telomerase is inactive following the stages early development (except in extreme cases such as cancer). Thus, if telomerase is not able to efficiently affect the DNA in the beginning of life, chromosomal instability becomes a grave possibility in individuals much earlier than would be expected.
A study shows that proliferative defects in DC skin keratinocytes are corrected by expression of the telomerase reverse transcriptase
Telomerase reverse transcriptase
Telomerase reverse transcriptase is a catalytic subunit of the enzyme telomerase. Its absence is associated with the disorder Cri du chat....
, TERT, or by activation of endogenous telomerase through expression of papillomavirus E6/E7 or the telomerase RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
component, TERC. Experimental Dermatology 2010; 19: 279–288
Genetics
Of the components of the telomerase RNA component (TERC), one of key importance is the box H/ACA domain. This H/ACA domain is responsible for maturation and stability of TERC and therefore of telomerase as a whole. The mammalMammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
ian H/ACA ribonucleoprotein
Ribonucleoprotein
Ribonucleoprotein is a nucleoprotein that contains RNA, i.e. it is an association that combines ribonucleic acid and protein together. A few known examples include the ribosome, the enzyme telomerase, vault ribonucleoproteins, and small nuclear RNPs , which are implicated in pre-mRNA splicing and...
contains four protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
subunits: dyskerin, Gar1, Nop10, and Nhp2. Mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in Nop10, Nhp2 and dyskerin1 have all been shown to lead to DKC-like symptoms.
Autosomal recessive form
The true phenotypePhenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
of DKC individuals may depend upon which protein has incurred a mutation. One documented autosomal recessive mutation in a family that carries DKC has been found in Nop10. Specifically, the mutation is a change of base from cytosine to thymine in a highly conserved region of the Nop10 sequence. This mutation, on chromosome 15
Chromosome 15 (human)
right|frame|Human chromosome 15Chromosome 15 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 15 spans about 106 million base pairs and represents between 3% and 3.5% of the total DNA in cells.Identifying genes on each chromosome is an...
, results in an amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
change from arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
to tryptophan
Tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
. Homozygous recessive individuals show the symptoms of dyskeratosis congenita in full. As compared to age-matched normal individuals, those suffering from DKC have telomeres of a much shorter length. Furthermore, heterozygotes, those who have one normal allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
and one coding for the disease, also show relatively shortened telomeres. The cause of this was determined to be a reduction in TERC levels in those with the Nop10 mutation. With TERC levels down, telomere maintenance, especially in development, would be presumed to suffer accordingly. This would lead to the telomere shortening described.
Nhp2 mutations are similar in characterization to Nop10. These mutations are also autosomal recessive with three specific single-nucleotide polymorphisms being recognized which result in dyskeratosis congenita. Also like Nop10, individuals with these Nhp2 mutations have a reduction in the amount of telomerase RNA component (TERC) present in the cell. Again it can be presumed that a reduction in TERC results in aberrant telomere maintenance and thus shortened telomeres. Those homozygous recessive for mutations in Nhp2 do show shorter telomeres when compared with age-matched normal individuals.
X-linked form
The best characterized form of dyskeratosis congenita is a result of one or more mutations in the long arm of the X chromosomeX chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
in the gene DKC1. This results in the X-linked recessive form of the disease wherein the major protein affected is dyskerin. Of the five mutations described by Heiss and colleagues in Nature Genetics, four were single nucleotide polymorphisms all resulting in the change of highly conserved amino acids
Conserved sequence
In biology, conserved sequences are similar or identical sequences that occur within nucleic acid sequences , protein sequences, protein structures or polymeric carbohydrates across species or within different molecules produced by the same organism...
. One case was an in-frame deletion resulting in the loss of a leucine
Leucine
Leucine is a branched-chain α-amino acid with the chemical formula HO2CCHCH2CH2. Leucine is classified as a hydrophobic amino acid due to its aliphatic isobutyl side chain. It is encoded by six codons and is a major component of the subunits in ferritin, astacin and other 'buffer' proteins...
residue
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
, also conserved in mammals. In three of the cases, the specific amino acids affected (phenylalanine
Phenylalanine
Phenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...
, proline
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
, glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
) are found in the same locus
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
in humans as they are in brewers yeast (S. Cerevisiae) and the brown rat
Brown Rat
The brown rat, common rat, sewer rat, Hanover rat, Norway rat, Brown Norway rat, Norwegian rat, or wharf rat is one of the best known and most common rats....
(R. Norvegicus). This establishes the sequence conservation and importance of dyskerin within the eukaryotes. The relevant nature of dyskerin throughout most species is to catalyze the post-transcriptional pseudouridylation
Pseudouridine
Pseudouridine is the C-glycoside isomer of the nucleoside uridine, and it is the most prevalent of the over one hundred different modified nucleosides found in RNA. Ψ is found in all species and in many classes of RNA except mRNA...
of specific uridine
Uridine
Uridine is a molecule that is formed when uracil is attached to a ribose ring via a β-N1-glycosidic bond.If uracil is attached to a deoxyribose ring, it is known as a deoxyuridine....
s found in non-coding RNAs, such as ribosomal RNA
Ribosomal RNA
Ribosomal ribonucleic acid is the RNA component of the ribosome, the enzyme that is the site of protein synthesis in all living cells. Ribosomal RNA provides a mechanism for decoding mRNA into amino acids and interacts with tRNAs during translation by providing peptidyl transferase activity...
(rRNA). Cbf5, the yeast analog of human dyskerin, is indeed known to be associated with the processing and maturation of rRNA. In humans this role can be attributed to dyskerin. Thus, the X-linked form of this disease may result in specific issues related to dysfunctional rRNA and perhaps a graver phenotype. Within the vertebrates, as opposed to single celled eukaryotes, dyskerin is a key component of the telomerase RNA component (TERC) in the form of the H/ACA motif. This X-linked variety, like the Nop10 and Nhp2 mutations, demonstrates shortened telomeres as a result of lower TERC concentrations.
Autosomal dominant form
The evidence supporting the importance of the H/ACA domain in human telomerase is abundant. At least one study has shown that these mutations affect telomerase activity by negatively affecting pre-RNP assembly and maturation of human telomerase RNA. Nonetheless, mutations which directly affect the telomerase RNA components would presumably exist and should also cause premature aging or DKC-like symptoms. Indeed, three families with mutations in the human TERC gene have been studied with intriguing results. In two of these families, two family-specific single nucleotide polymorphisms were present while in the other there persisted a large-scale deletion (821 base pairs of DNA) on chromosome 3Chromosome 3 (human)
Chromosome 3 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 3 spans almost 200 million base pairs and represents about 6.5 percent of the total DNA in cells....
which includes 74 bases coding for a section of the H/ACA domain. These three different mutations result in a mild form of dyskeratosis congenita which uniquely follows an autosomal dominant pattern of inheritance. Premature graying, early dental loss, predisposition to skin cancer, as well as shortening of telomere length continue to be characteristic of this disease.
Predisposition to cancer
Susceptibility to cancer seems counterintuitive because in many known cancers reactivation of telomerase is actually a required step for malignancy to evolve (See discussion here). In a disease where telomerase is affected, it does not seem to follow that cancer would be a complication to result. The authors note the paradoxParadox
Similar to Circular reasoning, A paradox is a seemingly true statement or group of statements that lead to a contradiction or a situation which seems to defy logic or intuition...
ical nature of cancer predisposition in individuals who seem to lack one of the required components for cancerous lesions. It is discussed that with reduced telomeres, chromosomes will likely be attached together at their ends through the non-homologous end joining
Non-homologous end joining
Non-homologous end joining is a pathway that repairs double-strand breaks in DNA. NHEJ is referred to as "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homologous recombination, which requires a homologous sequence to guide...
pathway (NHEJ). If this were a common enough occurrence, malignancy even without functional telomerase seems probable.