Prolidase deficiency (PD) is an extremely uncommon
autosomal
An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosomes ...
recessive
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and ...
disorder associated with
collagen metabolism
that affects connective tissues and thus a diverse array of organ systems more broadly, though it is extremely inconsistent in its expression.
Collagen is a structural protein found i.a. in bone, skin and connective tissues that is broken down into iminodipeptides at the end of its lifecycle. Of these dipeptides, those containing C-terminal
proline or
hydroxyproline
(2''S'',4''R'')-4-Hydroxyproline, or L-hydroxyproline ( C5 H9 O3 N), is an amino acid, abbreviated as Hyp or O, ''e.g.'', in Protein Data Bank.
Structure and discovery
In 1902, Hermann Emil Fischer isolated hydroxyproline from hydrolyzed gelatin ...
would normally be broken down further by the enzyme
Prolidase, recovering and thus recycling the constituent amino acids.
Due to a genetic defect, prolidase activity in individuals with PD is either knocked out or severely reduced. Those affected therefore eliminate excessive amounts of iminodipeptides in their urine,
wasting this precious resource, with debilitating effects.
Symptoms and signs
Prolidase deficiency generally becomes evident during infancy, but initial symptoms can first manifest anytime from birth to young adulthood. The condition results in a very diverse set symptoms,
the severity of which can vary significantly between patients, depending on the degree to which prolidase activity is hampered by the individual underlying mutation(s) in each case. It is even possible, though rare, for affected individuals to be asymptomatic, in which case the disorder can only be identified through laboratory screening of the prospective patient and/or their extended family.
One of the signature features of PD is the elimination of high quantities of peptides through urine.
In addition, most of those affected exhibit persistent skin lesions (starting from a mild rash) or ulcers, primarily on the legs and feet, the formation of which normally begins during childhood.
Clinically, these, among other dermatological issues, represent the most distinguishing and most frequent symptoms.
These may never recede, potentially leading to severe infections that can, in the worst case, necessitate amputation.
PD patients exhibit a weak immune system and markedly elevated vulnerability to infections in general, and particularly those of the respiratory system, leading some who suffer from PD to acquire recurrent lung disease. They may also have an enlarged spleen (splenomegaly), and on some occasions the spleen and liver may both be enlarged (hepatosplenomegaly).
Photosensitivity Photosensitivity is the amount to which an object reacts upon receiving photons, especially visible light. In medicine, the term is principally used for abnormal reactions of the skin, and two types are distinguished, photoallergy and phototoxici ...
and
hyperkeratosis
Hyperkeratosis is thickening of the stratum corneum (the outermost layer of the epidermis, or skin), often associated with the presence of an abnormal quantity of keratin,Kumar, Vinay; Fausto, Nelso; Abbas, Abul (2004) ''Robbins & Cotran Pathologi ...
have been associated with PD. Abnormal facial characteristics, consisting of pronounced eyes which are spaced far apart (
hypertelorism
Hypertelorism is an abnormally increased distance between two organs or bodily parts, usually referring to an increased distance between the orbits (eyes), or orbital hypertelorism. In this condition the distance between the inner eye corners as ...
), a high forehead, a compressed bridge of the nose or saddle nose, and a small lower jaw and chin (
micrognathia
Micrognathism is a condition where the jaw is undersized. It is also sometimes called mandibular hypoplasia. It is common in infants, but is usually self-corrected during growth, due to the jaws' increasing in size. It may be a cause of abnorma ...
), are also observed in the majority of cases.
Those affected by PD can also suffer intellectual disabilities (approx. 75% of recorded cases do) ranging from mild to severe – mental development during childhood may therefore progress more slowly.
Causes
Prolidase deficiency is the result of
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
s on the PEPD
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
, located on
chromosome 19
Chromosome 19 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 19 spans more than 58.6 million base pairs, the building material of DNA. It is considered the most gene-rich chromosom ...
and coding for the
prolidase Enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
, also known as peptidase-D.
At least 19 different mutations in the PEPD gene have been identified in individuals affected by the disorder.
Prolidase is involved in the degradation of certain iminodipeptides (those containing C-terminal
proline or
hydroxyproline
(2''S'',4''R'')-4-Hydroxyproline, or L-hydroxyproline ( C5 H9 O3 N), is an amino acid, abbreviated as Hyp or O, ''e.g.'', in Protein Data Bank.
Structure and discovery
In 1902, Hermann Emil Fischer isolated hydroxyproline from hydrolyzed gelatin ...
) formed during the breakdown of
collagen, recycling the constituent
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
s (proline and hydroxyproline) and making them available for the cell to reuse – not least in the synthesis of new collagen. This recycling by prolidase, seen in the image above, is essential for maintaining proline-based systems in the cell, such as the collagen-rich
extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide struc ...
(ECM), which serves to physically support the structure of internal organs and connective tissues. Inadequate recycling due to a dysfunctional prolidase enzyme, caused by an appropriate mutation in the pertinent gene, leads to the deterioration of that support structure and therefore the connective tissue of the skin, capillaries, and the lymphatic tissue, as is the case in PD.
In particular, it has been proposed that the buildup of non-degraded dipeptides might induce programmed cell-death (
apoptosis), whereafter the cell's contents would be expelled into the neighbouring tissue potentially resulting in inflammation and giving rise to the dermatological problems seen in PD. Similarly, a dysfunctional collagen metabolism will likely interfere with physiological remodelling processes of the extracellular matrix (which require collagen to be dynamically degraded and rebuilt), which might cause problems with the skin, as well.
The mental impairment observed in those with PD might reasonably arise from complications involving neuropeptides, proteins that have an abundance of proline and are involved with communication in the brain.
The condition is inherited in an autosomal recessive fashion, meaning that both copies of the gene contained in every cell (both
allele
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chro ...
s) are mutated. Each of the parents of the person who suffers from an autosomal recessive disorder possesses one copy of the mutant gene, but they usually do not exhibit the signs and symptoms of the disorder, as their other copy is functional and can compensate for any deleterious effects.
Diagnosis
PD diagnosis is based primarily on the presence and position of ulcers on the skin, as well as identifying particular protein markers in urine. To confirm the diagnosis, a blood test is required to measure prolidase activity.
Treatment
No curative treatment is available for prolidase deficiency at this time, although palliative treatment is possible to some extent.
The latter mainly focuses on treating the skin lesions through standard methods and stalling collagen degradation (or boosting prolidase performance, where possible), so as to keep the intracellular dipeptide levels low and give the cells time to resynthesise or absorb what proline they cannot recycle so as to be able to rebuild what collagen ''does'' degrade. Patients can be treated orally with ascorbate (a.k.a.
vitamin C
Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits and vegetables, also sold as a dietary supplement and as a topical 'serum' ingredient to treat melasma (dark pigment spots) a ...
, a cofactor of
prolyl hydroxylase
Procollagen-proline dioxygenase, commonly known as prolyl hydroxylase, is a member of the class of enzymes known as alpha-ketoglutarate-dependent hydroxylases. These enzymes catalyze the incorporation of oxygen into organic substrates through a mec ...
, an enzyme that hydroxylates proline, increasing collagen stability), manganese (a cofactor of prolidase), suppression of collagenase (a collagen degrading enzyme), and local applications of ointments that contain L-glycine and L-proline. The response to the treatment is inconsistent between affected individuals.
A therapeutic approach based on enzyme replacement (administering functional prolidase) is under consideration.
Due to the weakened immune response in PD cases, it is also of paramount importance to keep any infections under control, often with heavy antibiotics.
References
External links
Prolidase deficiencyon
OrphaNet
Orphanet is a knowledge base dedicated to rare diseases as well as corresponding diagnosis, orphan drugs, clinical trials and expert networks
The website is managed by a network of academic establishments from 40 countries, led by Inserm.
It c ...
{{Amino acid metabolic pathology
Amino acid metabolism disorders
Autosomal recessive disorders
Rare diseases
Skin conditions resulting from errors in metabolism