Potocki-Lupski syndrome
Encyclopedia
Potocki-Lupski syndrome, also known as dup(17)p11.2p11.2 syndrome, trisomy 17p11.2 or duplication 17p11.2 syndrome, is a contiguous gene syndrome
involving the microduplication of band
11.2 on the short arm of human chromosome 17
(17p11.2). The duplication was first described as a case study
in 1996. In 2000, the first study of the disease was released, and in 2007, enough patients had been gathered to complete a comprehensive study and give it a detailed clinical description. PTLS is named for two researchers involved in the latter phases, Drs. Lorraine Potocki and James R. Lupski
of the Baylor College of Medicine
.
PTLS was the first predicted reciprocal
of a homologous recombination
(microdeletion or microduplication
) where both reciprocal recombinations result in a contiguous gene syndrome. Its reciprocal disease is Smith-Magenis syndrome
(SMS), in which the chromosome portion duplicated in PTLS is deleted altogether.
Potocki-Lupski syndrome is considered a rare disease
, predicted to appear in at least 1 in 20,000 humans.
Symptoms of the syndrome include mild mental retardation
, autism
, and other disorders unrelated to the listed symptoms.
and mental retardation
. A key feature which appears in 80% of cases is autism spectrum disorder. Other unique features of Potocki-Lupski syndrome include infantile hypotonia, sleep apnea
, structural cardiovascular anomalies
, learning disabilities, attention-deficit disorder, obsessive-compulsive behaviours, malocclusion
s, short stature
and failure to thrive
.
After noting that autism is commonly associated with PTLS, researchers at the Centro de Estudios Científicos
and the Universidad Austral de Chile
genetically engineered a PTLS "model mouse
" where the syntenic chromosome segment was duplicated, and examined the social behaviours of these mice versus those without the anomaly (the "wild-type"). One human autism-related symptom is abnormal reciprocal
social interaction. The researchers observed that the genetically-engineered mice of both sexes had a slight (statistically insignificant
) impairment of their preference of a social target (i.e., a living, breathing mouse) over an inanimate one — the average human will prefer the social target — and preferred to explore newly-introduced mice instead of familiar ones, unlike the typical human and mouse preference of a friend over a stranger, demonstrating a change in their liking of social novelty. They also found that male mice, in some scenarios, showed increased anxiety
and dominant behaviour than the control group. Anatomically, the engineered mice had a decreased brain-to-body mass ratio and an alteration in the expression
of several genes in the hippocampus
.
mechanism. Both appear to involve a 1.3-3.7Mb chromosome section in 17p11.2
that includes the retinoic acid
inducible 1 (RAI1
) gene. Other candidate gene
s have been identified within the duplicated section, including SREBF1
, DRG2
, LLGL1
, SHMT1 and ZFP179.
In mice of the subfamily Murinae
, a 32-34cM
region of chromosome 11 is syntenic to 17p11.2, meaning that they contain the same genes in the same order and orientation. This conserved sequence has been exploited to learn more about SMS and PTLS. Through genetic studies on both laboratory mice and humans, it has been discovered that RAI1 is likely the gene responsible for these syndromes. For example, in one study, it was shown that mice with one copy of the RAI1 gene and 3 copies of each of the other 18 genes in the described translocated
region of chromosome 11 appeared and behaved like the control mice with the described region intact. In other words, RAI1 is dosage
-sensitive. This provides evidence that it is the number of RAI1 copies present that effects the symptoms of PTLS and SMS. It is therefore believed that RAI1 is the critical gene involved in these disorders; however, since no cases of RAI1 duplication alone have been identified, this has not been concluded.
One group has noted that, in a mouse model, the flanking genes in the duplicated segment were also overexpressed, suggesting some new candidates
for analysis, including MFAP4, TTC19 and GJA12.
(aCGH) may be used.
Contiguous gene syndrome
A contiguous gene syndrome is a syndrome caused by abnormalities of 2 or more genes that are located next to each other on a chromosome. Prader-Willi Syndrome, which is caused by the microdeletion of 15q11-13, is a common example. Prader-Willi syndrome occurs when the deletion occurs on the...
involving the microduplication of band
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
11.2 on the short arm of human chromosome 17
Chromosome 17 (human)
125px|rightChromosome 17 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 17 spans more than 81 million base pairs and represents between 2.5 and 3 % of the total DNA in cells.Identifying genes on each chromosome is an active area of...
(17p11.2). The duplication was first described as a case study
Case study
A case study is an intensive analysis of an individual unit stressing developmental factors in relation to context. The case study is common in social sciences and life sciences. Case studies may be descriptive or explanatory. The latter type is used to explore causation in order to find...
in 1996. In 2000, the first study of the disease was released, and in 2007, enough patients had been gathered to complete a comprehensive study and give it a detailed clinical description. PTLS is named for two researchers involved in the latter phases, Drs. Lorraine Potocki and James R. Lupski
James R. Lupski
James R. Lupski, M.D., Ph.D. is a Professor in the Department of Pediatrics at Baylor College of Medicine. Lupski suffers from a syndrome called Charcot-Marie-Tooth and has studied the condition as part of his research.-References:...
of the Baylor College of Medicine
Baylor College of Medicine
Baylor College of Medicine, located in the Texas Medical Center in Houston, Texas, USA, is a highly regarded medical school and leading center for biomedical research and clinical care...
.
PTLS was the first predicted reciprocal
Reciprocal
-In mathematics:*Multiplicative inverse, in mathematics, the number 1/x, which multiplied by x gives the product 1, also known as a reciprocal*Reciprocal rule, a technique in calculus for calculating derivatives of reciprocal functions...
of a homologous recombination
Homologous recombination
Homologous recombination is a type of genetic recombination in which nucleotide sequences are exchanged between two similar or identical molecules of DNA. It is most widely used by cells to accurately repair harmful breaks that occur on both strands of DNA, known as double-strand breaks...
(microdeletion or microduplication
Gene duplication
Gene duplication is any duplication of a region of DNA that contains a gene; it may occur as an error in homologous recombination, a retrotransposition event, or duplication of an entire chromosome.The second copy of the gene is often free from selective pressure — that is, mutations of it have no...
) where both reciprocal recombinations result in a contiguous gene syndrome. Its reciprocal disease is Smith-Magenis syndrome
Smith-Magenis syndrome
Smith–Magenis Syndrome is a developmental disorder that affects many parts of the body. The major features of this condition include mild to moderate mental retardation, distinctive facial features, sleep disturbances, and behavioral problems...
(SMS), in which the chromosome portion duplicated in PTLS is deleted altogether.
Potocki-Lupski syndrome is considered a rare disease
Rare disease
A rare disease, also referred to as an orphan disease, is any disease that affects a small percentage of the population.Most rare diseases are genetic, and thus are present throughout the person's entire life, even if symptoms do not immediately appear...
, predicted to appear in at least 1 in 20,000 humans.
Symptoms of the syndrome include mild mental retardation
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
, autism
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
, and other disorders unrelated to the listed symptoms.
Characteristics
Clinically, PTLS presents as a milder syndrome than SMS, with distinct characteristics, though PTLS can be mistaken for SMS. Both syndromes are characterized by multiple congenital abnormalitiesCongenital abnormality
A congenital anomaly is a condition which is present at the time of birth which varies from the standard presentation....
and mental retardation
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
. A key feature which appears in 80% of cases is autism spectrum disorder. Other unique features of Potocki-Lupski syndrome include infantile hypotonia, sleep apnea
Sleep apnea
Sleep apnea is a sleep disorder characterized by abnormal pauses in breathing or instances of abnormally low breathing, during sleep. Each pause in breathing, called an apnea, can last from a few seconds to minutes, and may occur 5 to 30 times or more an hour. Similarly, each abnormally low...
, structural cardiovascular anomalies
Congenital heart defect
A congenital heart defect is a defect in the structure of the heart and great vessels which is present at birth. Many types of heart defects exist, most of which either obstruct blood flow in the heart or vessels near it, or cause blood to flow through the heart in an abnormal pattern. Other...
, learning disabilities, attention-deficit disorder, obsessive-compulsive behaviours, malocclusion
Malocclusion
A malocclusion is a misalignment of teeth or incorrect relation between the teeth of the two dental arches. The term was coined by Edward Angle, the "father of modern orthodontics", as a derivative of occlusion, which refers to the manner in which opposing teeth meet.-Presentation:Most people have...
s, short stature
Short stature
Short stature refers to a height of a human being which is below expected. Shortness is a vague term without a precise definition and with significant relativity to context...
and failure to thrive
Failure to thrive
Failure to thrive is a medical term which is used in both pediatric and adult human medicine, as well as veterinary medicine ....
.
After noting that autism is commonly associated with PTLS, researchers at the Centro de Estudios Científicos
Centro de Estudios Científicos
Centro de Estudios Científicos also known by its acronym CECS is a private, non-profit corporation based in Valdivia, Chile, devoted to the development, promotion and diffusion of scientific research. CECs research areas include biophysics, molecular physiology, theoretical physics, glaciology and...
and the Universidad Austral de Chile
Universidad Austral de Chile
Southern University of Chile is a research university in Chile based in Valdivia although it has some institutions and careers in Puerto Montt. Founded by decree on 7 September 1954 it is one of the eight original Chilean Traditional Universities...
genetically engineered a PTLS "model mouse
Model organism
A model organism is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the organism model will provide insight into the workings of other organisms. Model organisms are in vivo models and are widely used to...
" where the syntenic chromosome segment was duplicated, and examined the social behaviours of these mice versus those without the anomaly (the "wild-type"). One human autism-related symptom is abnormal reciprocal
Reciprocal
-In mathematics:*Multiplicative inverse, in mathematics, the number 1/x, which multiplied by x gives the product 1, also known as a reciprocal*Reciprocal rule, a technique in calculus for calculating derivatives of reciprocal functions...
social interaction. The researchers observed that the genetically-engineered mice of both sexes had a slight (statistically insignificant
Statistical significance
In statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....
) impairment of their preference of a social target (i.e., a living, breathing mouse) over an inanimate one — the average human will prefer the social target — and preferred to explore newly-introduced mice instead of familiar ones, unlike the typical human and mouse preference of a friend over a stranger, demonstrating a change in their liking of social novelty. They also found that male mice, in some scenarios, showed increased anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
and dominant behaviour than the control group. Anatomically, the engineered mice had a decreased brain-to-body mass ratio and an alteration in the expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
of several genes in the hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
.
Molecular genetics
Both Potocki-Lupski and Smith-Magenis syndromes arise through a faulty non allelic homologous recombinationNon allelic homologous recombination
Non allelic homologous recombination is a form of homologous recombination that occurs between two lengths of DNA that have high sequence homology, but are not alleles....
mechanism. Both appear to involve a 1.3-3.7Mb chromosome section in 17p11.2
Chromosome 17 (human)
125px|rightChromosome 17 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 17 spans more than 81 million base pairs and represents between 2.5 and 3 % of the total DNA in cells.Identifying genes on each chromosome is an active area of...
that includes the retinoic acid
Retinoic acid
Retinoic acid is a metabolite of vitamin A that mediates the functions of vitamin A required for growth and development. Retinoic acid is required in chordate animals which includes all higher animals from fishes to humans...
inducible 1 (RAI1
RAI1
RAI1 is a transcription factor associated with Smith-Magenis syndrome. It is known as retinoic acid induced 1.-External links:*...
) gene. Other candidate gene
Candidate gene
A candidate gene is a gene, located in a chromosome region suspected of being involved in the expression of a trait such as a disease, whose protein product suggests that it could be the gene in question...
s have been identified within the duplicated section, including SREBF1
SREBF1
Sterol regulatory element-binding transcription factor 1 also known as sterol regulatory element-binding protein 1 is a protein that in humans is encoded by the SREBF1 gene....
, DRG2
DRG2
Developmentally-regulated GTP-binding protein 2 is a protein that in humans is encoded by the DRG2 gene.-Further reading:...
, LLGL1
LLGL1
Lethal giant larvae protein homolog 1 is a protein that in humans is encoded by the LLGL1 gene.-Further reading:...
, SHMT1 and ZFP179.
In mice of the subfamily Murinae
Murinae
The Old World rats and mice, part of the subfamily Murinae in the family Muridae, comprise at least 519 species. This subfamily is larger than all mammal families except the Cricetidae and Muridae, and is larger than all mammal orders except the bats and the remainder of the...
, a 32-34cM
Centimorgan
In genetics, a centimorgan or map unit is a unit of recombinant frequency for measuring genetic linkage, defined as that distance between chromosome positions for which the expected average number of intervening chromosomal crossovers in a single generation is 0.01. It is often used to infer...
region of chromosome 11 is syntenic to 17p11.2, meaning that they contain the same genes in the same order and orientation. This conserved sequence has been exploited to learn more about SMS and PTLS. Through genetic studies on both laboratory mice and humans, it has been discovered that RAI1 is likely the gene responsible for these syndromes. For example, in one study, it was shown that mice with one copy of the RAI1 gene and 3 copies of each of the other 18 genes in the described translocated
Chromosomal translocation
In genetics, a chromosome translocation is a chromosome abnormality caused by rearrangement of parts between nonhomologous chromosomes. A gene fusion may be created when the translocation joins two otherwise separated genes, the occurrence of which is common in cancer. It is detected on...
region of chromosome 11 appeared and behaved like the control mice with the described region intact. In other words, RAI1 is dosage
Gene dosage
Gene dosage is the number of copies of a gene present in a cell or nucleus. An increase in gene dosage can cause higher levels of gene product if the gene is not subject to regulation from elsewhere in the body....
-sensitive. This provides evidence that it is the number of RAI1 copies present that effects the symptoms of PTLS and SMS. It is therefore believed that RAI1 is the critical gene involved in these disorders; however, since no cases of RAI1 duplication alone have been identified, this has not been concluded.
One group has noted that, in a mouse model, the flanking genes in the duplicated segment were also overexpressed, suggesting some new candidates
Candidate gene
A candidate gene is a gene, located in a chromosome region suspected of being involved in the expression of a trait such as a disease, whose protein product suggests that it could be the gene in question...
for analysis, including MFAP4, TTC19 and GJA12.
Diagnosis
The duplication involved in PTLS is usually large enough to be detected through G-banding alone, though there is a high false negative rate. To ascertain the diagnosis when karyotyping results are unclear or negative, more sophisticated techniques such as subtelomeric fluorescent in-situ hybridization analysis and array comparative genomic hybridizationArray comparative genomic hybridization
Array-comparative genomic hybridization is a technique to detect genomic copy number variations at a higher resolution level than chromosome-based comparative genomic hybridization .-Process:DNA from...
(aCGH) may be used.
External links
- OMIM entry for Potocki-Lupski syndrome
- Potocki-Lupski (dup17p11.2) Syndrome — hosted by the Baylor College of MedicineBaylor College of MedicineBaylor College of Medicine, located in the Texas Medical Center in Houston, Texas, USA, is a highly regarded medical school and leading center for biomedical research and clinical care...
, home of both Potoski and LupskiJames R. LupskiJames R. Lupski, M.D., Ph.D. is a Professor in the Department of Pediatrics at Baylor College of Medicine. Lupski suffers from a syndrome called Charcot-Marie-Tooth and has studied the condition as part of his research.-References:...