Table 2.
Hereditary disorders associated to reduced synthesis or excessive degradation of specific collagen types.
| Disorder | Genetic Alteration | Link with the Disorder | Major Clinical Features a |
|---|---|---|---|
| Autosomal recessive dystrophic epidermolysis bullosa (RDEB) | A defect in collagenase MMP1 (*120353) has been implicated in RDEB (#226600). An association between disease severity and specific SNP in MMP1 gene (*120353) was found in three affected members of one family and in a cohort of 31 unrelated French RDEB patients [136]. The SNP results in increased transcript and active MMP1 protein levels. | COL7 is susceptible to degradation by the collagenase matrix metalloproteinases-1 (MMP1). An imbalance between COL7 synthesis and degradation could conceivably worsen the RDEB phenotype. | Patients with RDEB present generalized blisters at birth that result in extensive scarring and pseudosyndactyly. After birth, extensive blisters may affect the mucous membranes particularly the oral cavity, oesophagus and anal canal. Caused by chronic blood loss, inflammation, infection and poor nutrition, patients develop anaemia, failure to thrive, delayed puberty and osteoporosis. Patients usually do not survive more than 30 years due to severe renal complications or aggressive squamous cell carcinoma arising in the areas of repeated scarring [154]. |
| Aneurysm, abdominal aortic (AAA) | Mapped loci for AAA (#100070) include AAA1 (*100070) on chromosome 19q13, AAA2 (*609782) on chromosome 4q31, AAA3 (*611891) on chromosome 9p21 and AAA4 (*614375) on chromosome 12q13. Inheritance is autosomal dominant. |
Several studies pointed to a role of MMPs in the end-stage of AAA. MMPs are enzymes capable of degrading connective tissue that may affect arterial walls by degrading collagens and other ECM components. Polymorphisms in MMP2, MMP3, MMP9 and MMP13 genes result in increased protein levels significantly associated to AAA risk. | AAA is characterized by chronic inflammation and ECM degradation of the aortic wall. The main symptoms of this condition are dysphasia, frontotemporal cerebral atrophy and frontotemporal dementia, speech disorder, memory impairment [155]. |
| Trichothiodystrophy 1, photosensitive form (TTD1) | TTD1 (#601675) is caused by homozygous or compound heterozygous mutation in the ERCC2/XPD gene (*126340) on chromosome 19q13. The gene encodes a helicase subunit of the transcription/repair factor TFIIH. The inheritance is autosomal recessive. | A reduced expression of COL6A1 (*120220), an abundant collagen of skin and connective tissue, has been shown in the skin of TTD patients with mutations in the ERCC2/XPD gene [156]. It has been shown that specific transcription deregulations in the cells of TTD patients with mutations in the ERCC2/XPD gene result in the overexpression of MMP1 gene. This event leads to hyper-secretion of active MMP1 enzyme and degradation of collagen type I in the dermis of TTD patient skin [157]. |
TTD is characterized by hair abnormalities, physical and mental retardation, ichthyosis, signs of premature aging and cutaneous photosensitivity. The clinical spectrum of TTD varies widely from patients with only brittle, fragile hair to patients with the most severe neuroectodermal symptoms. TTD patients present sulphur-deficient brittle hair with a diagnostic alternating light and dark banding pattern (called ‘tiger’ tail banding) under polarizing microscopy. Common additional clinical features include collodion baby, characteristic facies, ocular abnormalities, short stature, decreased fertility and recurrent infections. TTD patients present a 20-fold higher mortality compared to the US general population [158,159]. |
| Atopic dermatitis (ATOD) | ATOD (#603165) is caused by the presence of a specific SNP (rs4688761) in COL29A1 gene (*611916), which encodes a novel epidermal collagen. The gene is on chromosome 3q22.1. Inheritance is autosomal dominant. |
COL29A1 shows a specific gene expression pattern with the highest transcript levels in skin, lung and gastrointestinal tract, which are the major sites of allergic disease manifestation. Lack of COL29A1 expression in the outer layers of the epidermis of ATOD patients points to a role of collagen XXIX in epidermal integrity, whose breakdown is a clinical hallmark of AD [160]. | ATOD is a chronic inflammatory skin disease characterized by intensely itchy skin lesions. The onset of disease is typically observed during the first two years of life [161]. The hallmarks of atopic dermatitis are a chronic relapsing form of skin inflammation, a disturbance of epidermal barrier function that culminates in dry skin and IgE-mediated sensitization to food and environmental allergens. |
| Bruck syndrome (BRKS) | BRKS is a very rare autosomal recessive syndrome. Two forms are found: BRKS1 (#259450) is caused by mutations in FKBP10 (*607067) gene whereas BRKS2 (#609220) by mutations in PLOD2 (*601865) gene. | BRKS is characterized by bone fragility associated with congenital joint contractures. Patients commonly show short stature, skull wormian bones and kyphoscoliosis. Most cases had normal teeth, white sclera, normal cognitive functions and normal hearing. A few cases had dysmorphic features including triangular face and brachycephaly [162]. | |
| Bruck syndrome 1 (BRKS1) | BRKS1 (#259450) is caused by homozygous mutations in FKBP10 gene (*607063) on chromosome 17q21 resulting in FKBP65 loss of function. Inheritance is autosomal recessive. |
Mutations in FKBP10 result in delay of type 1 procollagen secretion, incomplete stabilization of collagen trimer, reduced hydroxylation of the telopeptide lysyl residue (involved in intermolecular collagen cross-linking). | BRKS1 patients have short stature, high incidence of joint contractures, frequent fractures and scoliosis. |
| Bruck syndrome 2 (BRKS2) | BRKS2 (#609220) is caused by homozygous mutation in PLOD2 gene (*601865) on chromosome 3q24. Inheritance is autosomal recessive. | PLOD2 encodes the telopeptide lysyl hydroxylase required for the triple-helical cross-linking of collagen molecules. Mutations in this gene affect the instalment and secretion of collagen fibres from osteoblasts [163]. | No phenotypic differences between BRKS1 and BRKS2 have been reported. |
| Ehlers-Danlos syndrome (EDS) subtypes | The EDS subtypes are due to mutations in several genes, including PLOD1, FKBP14, ADAMTS2, ZNF469 and PRDM5. | ||
| EDS Kyphoscoliotic Type 1 (EDSKSCL1) | EDSKSCL1 (#225400) previously designated EDS6, is caused by homozygous or compound heterozygous mutation in the PLOD1 (*153454) gene on chromosome 1p36. Inheritance is autosomal recessive. |
PLOD1 encodes a lysyl hydroxylase that catalyses the hydroxylation of lysine residues in X-lys-gly sequences of collagens and other proteins with collagen-like domains. This hydroxylation is essential for the stability of intermolecular collagen crosslinks. |
EDSKSCL1 is characterized by skin fragility (easy bruising, friable skin, poor wound healing, widened atrophic scarring), scleral and ocular fragility/rupture, microcornea, facial dysmorphology. General features also include congenital muscle hypotonia, congenital or early onset kyphoscoliosis, joint hypermobility with subluxations or dislocations of shoulders, hips and knees [164]. |
| EDS Kyphoscoliotic Type, 2 (EDSKSCL2) | EDSKSCL2 (#614557) is caused by homozygous or compound heterozygous mutations in FKBP14 gene (*614505) on chromosome 7p15. Inheritance is autosomal recessive. |
FKBP14 is an ER-resident protein belonging to the family of FK506-binding peptidyl-prolyl cis–trans isomerases (PPIases). It catalyses the folding of COL3 and interacts with COL3, COL4 and COLX [165]. | EDSKSCL2 is characterised by congenital hearing impairment (sensorineural, conductive, or mixed), follicular hyperkeratosis, muscle atrophy, bladder diverticula. |
| EDS dermatosparaxis Type (EDSDERMS) | EDSDERMS (#225410) is caused by mutation in ADAMTS2 (*604539) gene on chromosome 5q35. Inheritance is autosomal recessive. |
ADAMTS2 encodes a procollagen protease that takes part to the processing of type I procollagen. | Dermatosparaxis means ‘tearing of skin.’ Patients present extreme skin laxity and fragility, easy bruising, extensive scar formation and joint laxity. Blue sclerae, micrognathia, umbilical hernia and postnatal growth retardation are reported [164]. |
| Brittle Cornea Syndrome1 (BCS1) | BCS1 (#229200) can be caused by homozygous mutation in the ZNF469 gene (*612078) on chromosome 16q24. Inheritance is autosomal recessive. | ZNF469 encodes a zinc-finger protein that likely acts as a transcription factor or extra-nuclear regulator factor for the synthesis or organization of collagen fibres. | BCS1 and BCS2 are associated with retinal microvascular abnormalities, keratoconus or keratoglobus, blue sclerae, extreme corneal thinning and a high risk of corneal rupture. Hyperelasticity of the skin without excessive fragility and hypermobility of the joints are other hallmarks of the disease [164]. |
| Brittle Cornea Syndrome2 (BCS2) | BCS2 (#614170) is caused by mutation in PRDM5 gene (*614161) on chromosome 4q27. Inheritance is autosomal recessive. | PRDM5 seems to regulate the expression of proteins involved in extracellular matrix development and maintenance, including COL4A1 and COL11A1. | BCS2 features overlap with BCS1. Systemic abnormalities included increased skin laxity, pectus excavatum, scoliosis, congenital hip dislocation, recurrent shoulder dislocation, high-frequency hearing loss, high-arched palate and mitral valve prolapse [166]. |
| CUTIS LAXA | Cutis laxa can be caused by mutations in either PYCR1 (*179035) or ALDH18A1 (#614438) gene. | Cutis laxa is a rare skin disorder characterized by wrinkled, redundant, inelastic and sagging skin due to defective synthesis of elastic fibres and other proteins of the ECM [167]. | |
| Cutis Laxa, autosomal recessive Type IIB (ARCL2B) | ARCL2B (#612940) is caused by homozygous or compound heterozygous mutation in the PYCR1 gene (*179035) on chromosome 17q25.3. Inheritance is autosomal recessive. | PYCR1 encodes the enzyme pyrroline-5-carboxylate reductase1, which catalyses the last step of proline synthesis. PYCR1 deficiency can affect the proper collagen formation. | ARCL2 is a more benign form of cutis laxa present at birth. Growth and developmental delay and skeletal anomalies are reported. Intellectual deficit and seizures have been reported in older patients [167]. Systemic manifestations are mild whereas pulmonary emphysema and cardiac anomalies are rare. |
| Cutis Laxa, autosomal recessive Type IIIB (ARCL3B) | ARCL3B (#614438) is caused by mutation in PYCR1 gene (179035) on chromosome 17q25. Inheritance is autosomal recessive. | ARCL3B is a rare autosomal recessive disorder characterized by a progeria-like appearance with distinctive facial features, sparse hair, ophthalmologic abnormalities and intrauterine growth retardation [168]. | |
| Cutis Laxa, autosomal recessive, Type IIIA (ARCL3A) | ARCL3A (#219150) is caused by mutation in the ALDH18A1 gene (*138250) on chromosome 10q24. Inheritance is autosomal recessive. | The protein encoded by ALDH18A1 catalyses the reduction of glutamate to delta1-pyrroline-5-carboxylate, a critical step in the de novo biosynthesis of proline, ornithine and arginine. | ARCL3A is characterized by cutis laxa (a progeria-like appearance) and ophthalmologic abnormalities [169]. In some case, additional features have been described, including delayed development, intellectual disability, seizures and problems with movement that can worsen over time. |
| Cutis Laxa, autosomal dominant, Type III (ADCL3) | ADCL3 (#616603) is caused by mutation in ALDH18A1 gene (*138250) on chromosome 10q24. Inheritance is autosomal dominant. | ADCL3 has a progeroid appearance characterized by thin skin with visible veins and wrinkles, ophthalmological abnormalities, clenched fingers, pre- and postnatal growth retardation and moderate intellectual disability. Patients also exhibit a combination of muscular hypotonia with brisk muscle reflexes [170]. | |
| Keratoconus-1 (KTCN1) | KTCN1 (#148300) is caused by heterozygous mutation in the Visual system homeobox gene 1 (VSX1, *605020) gene on 20p11 chromosome. Inheritance is autosomal dominant. |
VSX1 encodes a homeoprotein that regulates the expression of the cone opsin genes early in development. Recent studies showed that the structural deformity of the cornea in KCTN patients may be due to reduced expression of collagens (COL1A1 and COL4A1) and LOX family oxidases, as well as on the concomitant increased expression of MMP9 [171]. |
KTCN1 is the most common corneal dystrophy. It is a bilateral, often asymmetrical, non-inflammatory progressive corneal ectasia that causes visual morbidity. In affected individuals, the cornea becomes progressively thin and conical in shape, resulting in myopia, irregular astigmatism and corneal scarring. It typically appears in the teenage years and then it progresses until the third and fourth decades. No specific treatment exists except corneal transplantation when visual acuity can no longer be corrected by contact lenses [172]. |
a Information mainly based on OMIM, the Online Mendelian Index in Man at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM. Grey and white rows are used to distinguish the different disorders. Causative genes are in bold. Abbreviations: the acronyms of the pathologies are all specified inside the Table.