Potocki–Lupski Syndrome
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Potocki–Lupski syndrome (PTLS), also known as dup(17)p11.2p11.2 syndrome, trisomy 17p11.2 or duplication 17p11.2 syndrome, is a
contiguous gene syndrome A contiguous gene syndrome (CGS), also known as a contiguous gene deletion syndrome, is a clinical phenotype caused by a chromosomal abnormality, such as a deletion or duplication that removes several genes lying in close proximity to one another ...
involving the microduplication of
band Band or BAND may refer to: Places *Bánd, a village in Hungary * Band, Iran, a village in Urmia County, West Azerbaijan Province, Iran * Band, Mureș, a commune in Romania * Band-e Majid Khan, a village in Bukan County, West Azerbaijan Province, ...
11.2 on the short arm of human
chromosome 17 Chromosome 17 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 17 spans more than 84 million base pairs (the building material of DNA) and represents between 2.5 and 3% of the total DN ...
(17p11.2). The duplication was first described as a
case study A case study is an in-depth, detailed examination of a particular case (or cases) within a real-world context. For example, case studies in medicine may focus on an individual patient or ailment; case studies in business might cover a particular f ...
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 (born February 22, 1957) is the Cullen Endowed Chair in Molecular Genetics and Professor in the Department of Pediatrics at Baylor College of Medicine The Baylor College of Medicine (BCM) is a private medical school in Houst ...
of
Baylor College of Medicine The Baylor College of Medicine (BCM) is a private medical school in Houston, Texas, United States. Originally as the Baylor University College of Medicine from 1903 to 1969, the college became independent with the current name and has been se ...
. PTLS was the first predicted
reciprocal Reciprocal may refer to: In mathematics * Multiplicative inverse, in mathematics, the number 1/''x'', which multiplied by ''x'' gives the product 1, also known as a ''reciprocal'' * Reciprocal polynomial, a polynomial obtained from another pol ...
of a
homologous recombination Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in Cell (biology), cellular organi ...
(
microdeletion In genetics, a deletion (also called gene deletion, deficiency, or Deletion anomaly, deletion mutation) (sign: delta (letter), Δ) is a mutation (a genetic aberration) in which a part of a chromosome or a sequence of DNA is left out during DNA rep ...
or microduplication) where both reciprocal recombinations result in a contiguous gene syndrome. Its reciprocal disease is
Smith–Magenis syndrome Smith–Magenis syndrome (SMS), also known as 17p-microdeletion syndrome, is a microdeletion syndrome characterized by an abnormality in the short (p) arm of chromosome 17. It has features including intellectual disability, facial abnormalities, ...
(SMS), in which the chromosome portion duplicated in PTLS is deleted altogether. Potocki–Lupski syndrome is considered a
rare disease A rare disease is any disease that affects a small percentage of the population. In some parts of the world, the term orphan disease describes a rare disease whose rarity results in little or no funding or research for treatments, without financi ...
, predicted to appear in at least 1 in 20,000 humans. Symptoms of the syndrome include
intellectual disability Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...
,
autism Autism, also known as autism spectrum disorder (ASD), is a neurodevelopmental disorder characterized by differences or difficulties in social communication and interaction, a preference for predictability and routine, sensory processing d ...
, and other disorders unrelated to the listed symptoms.


Presentation

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 abnormalities A birth defect is an abnormal condition that is present at birth, regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can range from mild to severe. Birth de ...
and
intellectual disability Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...
. A key feature which appears in 80% of cases is
autism spectrum disorder Autism, also known as autism spectrum disorder (ASD), is a neurodevelopmental disorder characterized by differences or difficulties in social communication and interaction, a preference for predictability and routine, sensory processing di ...
. Other unique features of Potocki–Lupski syndrome include infantile hypotonia,
sleep apnea Sleep apnea (sleep apnoea or sleep apnœa in British English) is a sleep-related breathing disorder in which repetitive Apnea, pauses in breathing, periods of shallow breathing, or collapse of the upper airway during sleep results in poor vent ...
, structural cardiovascular anomalies,
cognitive deficit Cognitive impairment is an inclusive term to describe any characteristic that acts as a barrier to the cognition process or different areas of cognition. Cognition, also known as cognitive function, refers to the mental processes of how a person ...
s, abnormal
social behavior Social behavior is behavior among two or more organisms within the same species, it encompasses any behavior in which one member affects another. Social behavior can be seen as similar to an exchange of goods, with the expectation that when you ...
s,
learning disabilities Learning disability, learning disorder, or learning difficulty (British English) is a condition in the brain that causes difficulties comprehending or processing information and can be caused by several different factors. Given the "difficulty ...
, attention-deficit disorder, obsessive-compulsive behaviours,
malocclusion In orthodontics, a malocclusion is a misalignment or incorrect relation between the teeth of the upper and lower dental arches when they approach each other as the jaws close. The English-language term dates from 1864; Edward Angle (1855–1 ...
s,
short stature Short stature refers to a height of a human which is below typical. Whether a person is considered short depends on the context. Because of the lack of preciseness, there is often disagreement about the degree of shortness that should be called ...
and
failure to thrive Failure to thrive (FTT), also known as weight faltering or faltering growth, indicates insufficient weight gain or absence of appropriate physical growth in children. FTT is usually defined in terms of weight, and can be evaluated either by a low ...
. After noting that autism is commonly associated with PTLS, researchers at the Centro de Estudios Científicos and the
Austral University of Chile Austral University of Chile ( or UACh) is a Chilean research university based primarily in Valdivia, with satellite campuses in Puerto Montt and Coyhaique. Founded on September 7, 1954, it is one of the eight original Chilean Traditional Universi ...
genetically engineered Genetic engineering, also called genetic modification or genetic manipulation, is the modification and manipulation of an organism's genes using technology. It is a set of technologies used to change the genetic makeup of cells, including th ...
a PTLS " model mouse" where the syntenic chromosome segment was duplicated, and examined the
social behaviour Social behavior is behavior among two or more organisms within the same species, it encompasses any behavior in which one member affects another. Social behavior can be seen as similar to an exchange of goods, with the expectation that when you ...
s of these mice versus those without the anomaly (the "
wild-type The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, " ...
"). One human autism-related symptom is abnormal
reciprocal Reciprocal may refer to: In mathematics * Multiplicative inverse, in mathematics, the number 1/''x'', which multiplied by ''x'' gives the product 1, also known as a ''reciprocal'' * Reciprocal polynomial, a polynomial obtained from another pol ...
social interaction A social relation is the fundamental unit of analysis within the social sciences, and describes any voluntary or involuntary interpersonal relationship between two or more conspecifics within and/or between groups. The group can be a language or ...
. The researchers observed that the genetically-engineered mice of both sexes had a slight (
statistically insignificant In statistical hypothesis testing, a result has statistical significance when a result at least as "extreme" would be very infrequent if the null hypothesis were true. More precisely, a study's defined significance level, denoted by \alpha, is the ...
) 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 is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...
and dominant behaviour than the
control group In the design of experiments, hypotheses are applied to experimental units in a treatment group. In comparative experiments, members of a control group receive a standard treatment, a placebo, or no treatment at all. There may be more than one tr ...
. Anatomically, the engineered mice had a decreased brain-to-body mass ratio and an alteration in the expression of several genes in the
hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...
.


Molecular genetics

Both Potocki–Lupski and Smith–Magenis syndromes arise through a faulty
non-allelic homologous recombination Non-allelic homologous recombination (NAHR) is a form of homologous recombination that occurs between two lengths of DNA that have high sequence similarity, but are not alleles. It usually occurs between sequences of DNA that have been previously ...
mechanism. Both appear to involve a 1.3-3.7 Mb chromosome section in 17p11.2 that includes the ''
retinoic acid Retinoic acid (simplified nomenclature for all-''trans''-retinoic acid) is a metabolite of vitamin A1 (all-''trans''-retinol) that is required for embryonic development, male fertility, regulation of bone growth and immune function. All-''trans ...
inducible 1'' ('' RAI1'') gene. Other
candidate gene The candidate gene approach to conducting genetic association studies focuses on associations between genetic variation within pre-specified genes of interest, and Phenotype (clinical medicine), phenotypes or disease states. This is in contrast to ...
s have been identified within the duplicated section, including '' SREBF1'', '' DRG2'', '' LLGL1'', '' SHMT1'' and '' ZFP179''. In mice of the subfamily
Murinae The Old World rats and mice, part of the subfamily Murinae in the family Muridae, comprise at least 519 species. Members of this subfamily are called murines. In terms of species richness, this subfamily is larger than all mammal families excep ...
, a 32-34 cM 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 The laboratory mouse or lab mouse is a small mammal of the order Rodentia which is bred and used for scientific research or feeders for certain pets. Laboratory animal sources for these mice are usually of the species ''Mus musculus''. They a ...
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 2 copies 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 affects 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 A candidate, or nominee, is a prospective recipient of an award or honor, or a person seeking or being considered for some kind of position. For example, one can be a candidate for membership in a group or election to an office, in which case a ...
for analysis, including '' MFAP4'', '' TTC19'' and '' GJA12''.


Diagnosis

The duplication involved in PTLS is usually large enough to be detected through
G-banding G-banding, G banding or Giemsa banding is a technique used in cytogenetics to produce a visible karyotype by staining condensed chromosomes. It is the most common chromosome banding method. It is useful for identifying genetic diseases (mainly ch ...
alone, though there is a high
false negative A false positive is an error in binary classification in which a test result incorrectly indicates the presence of a condition (such as a disease when the disease is not present), while a false negative is the opposite error, where the test resu ...
rate. To ascertain the diagnosis when
karyotyping A karyotype is the general appearance of the complete set of chromosomes in the cells of a species or in an individual organism, mainly including their sizes, numbers, and shapes. Karyotyping is the process by which a karyotype is discerned by de ...
results are unclear or negative, more sophisticated techniques such as subtelomeric fluorescent in-situ hybridization analysis and array comparative genomic hybridization (aCGH) may be used.


Management


See also

* Chromosome nomenclature * Low copy repeats


References


External links

{{DEFAULTSORT:Potocki-Lupski syndrome Rare syndromes Congenital disorders