Collagen Type VI-Related Disorders
Anne Katrin Lampe, MD, Kevin M Flanigan, MD, Katharine Mary Bushby, MD, MBCHB FRCP, and Debbie Hicks, PhD.
Author InformationInitial Posting: June 25, 2004; Last Update: August 9, 2012.
Estimated reading time: 26 minutes
Summary
Clinical characteristics.
Collagen type VI-related disorders represent a continuum of overlapping phenotypes with Bethlem myopathy at the mild end, Ullrich congenital muscular dystrophy (CMD) at the severe end, and two rare, less well-defined disorders – autosomal dominant limb-girdle muscular dystrophy and autosomal recessive myosclerosis myopathy – in between. Although Bethlem myopathy and Ullrich CMD were defined long before their molecular basis was known, they remain useful for clarification of prognosis and management.
Bethlem myopathy, characterized by the combination of proximal muscle weakness and variable contractures, affects most frequently the long finger flexors, elbows, and ankles. Onset may be prenatal (characterized by decreased fetal movements), neonatal (hypotonia or torticollis), in early childhood (delayed motor milestones, muscle weakness, and contractures), or in adulthood (proximal weakness and Achilles tendon or long finger flexor contractures). Because of slow progression, more than two thirds of affected individuals over age 50 years rely on supportive means for outdoor mobility. Respiratory involvement is rare and appears to be related to more severe muscle weakness in later life.
Ullrich CMD is characterized by congenital weakness and hypotonia, proximal joint contractures, and striking hyperlaxity of distal joints. Some affected children acquire the ability to walk independently; however, progression of the disease often results in later loss of ambulation. Early and severe respiratory involvement may require ventilatory support in the first or second decade of life.
Diagnosis/testing.
Diagnosis depends on typical clinical features; normal or only mildly elevated serum creatine kinase concentration; suggestive pattern on muscle magnetic resonance imaging (MRI); muscle biopsy with collagen VI immunolabeling (for suspected Ullrich CMD) or skin biopsy and dermal fibroblast culture with collagen VI immunolabeling (for suspected Bethlem myopathy); and molecular genetic testing of COL6A1, COL6A2, and COL6A3, the three genes encoding the three collagen VI peptide chains.
Management.
Treatment of manifestations: As needed based on clinical findings: physiotherapy regarding stretching exercises, splinting, and mobility aids; orthopedic assessment if surgery for Achilles tendon contractures is being considered; therapy for scoliosis. Respiratory: evaluation for nocturnal hypoventilation; prophylaxis of chest infections with vaccination and physiotherapy; aggressive treatment of pulmonary infections. Nutrition: assessment of nutritional status and growth; management of feeding difficulties.
Surveillance: Routine assessment of: muscle weakness, scoliosis, joint contractures, and mobility; respiratory function; and nutritional status.
Genetic counseling.
The Bethlem myopathy phenotype is usually inherited in an autosomal dominant manner and the UMD phenotype is usually inherited in an autosomal recessive manner; however, exceptions occur. In the few cases reported to date, it appears that autosomal dominant limb-girdle muscular dystrophy is inherited in an autosomal dominant manner and the myosclerosis myopathy phenotype is inherited in an autosomal recessive manner. Carrier testing for autosomal recessive collagen VI-related disorders and prenatal testing are possible if the pathogenic variants have been identified in an affected family member.
Diagnosis
The collagen type VI-related disorders, caused by mutation of COL6A1, COL6A2, or COL6A3, represent a clinical spectrum including Bethlem myopathy at the mild end, Ullrich congenital muscular dystrophy (CMD) at the severe end, and two less well-defined disorders – autosomal dominant limb-girdle muscular dystrophy and autosomal recessive myosclerosis myopathy – in between.
Note: Although these phenotypes are now recognized to comprise a continuum of overlapping phenotypes, the clinical designations are useful for clarification of prognosis and management.
Clinical findings
Bethlem myopathy is recognized clinically by the combination of the following [Jöbsis et al 1999]:
Ullrich congenital muscular dystrophy (CMD) is recognized clinically by the combination of the following [Voit 1998, Muntoni et al 2002]:
Congenital weakness and hypotonia
Proximal joint contractures
Striking hyperlaxity of distal joints
Note: As Bethlem myopathy may also present at birth, it may be difficult to categorize a neonate who has no family history of muscle disease into either Bethlem myopathy or Ullrich CMD initially; however, with time the stable acquisition of ambulation allows the diagnosis of Bethlem myopathy.
In both Bethlem myopathy and Ullrich CMD:
Muscle MRI. Bethlem myopathy and Ullrich CMD have distinct patterns of muscle involvement, although some overlap exists [Mercuri et al 2005].
Transverse T1-weighted images through thigh muscles in four individuals with Bethlem myopathy (a-d). Note the relative sparing of the central part of the vastus lateralis with a rim of increased signal at the periphery of the muscle and the prominent (more...)
Transverse T1-weighted images through thigh muscles in four individuals with Ullrich CMD. Note the diffuse involvement of the thigh with relative sparing of sartorius, gracilis, and rectus femoris (arrows) in three young affected individuals (a-c). A (more...)
Tissue studies
Bethlem myopathy
Dermal fibroblasts in Bethlem myopathy A. Normal control with collagen VI labeling with antibody
Ullrich CMD
Muscle biopsy more commonly shows dystrophic features with degeneration and regeneration and replacement of muscle with fat and fibrous connective tissue. Collagen VI immunolabeling from the endomysium and basal lamina ranges from absent to moderately or markedly reduced, but may be normal around capillaries [
Higuchi et al 2003].
Molecular Genetic Testing
Genes.
COL6A1, COL6A2, and COL6A3 are the three genes in which pathogenic variants are known to cause collagen type VI-related disorders.
Table 1.
Molecular Genetic Testing Used in Collagen VI-Related Disorders
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Gene 1 | Proportion of Collagen VI-Related Disorders Attributed to Pathogenic Variants in This Gene 2 | Method | Variants Detected 3 |
---|
COL6A1 | 38% | Sequence analysis 4 | Sequence variants |
Duplication/deletion analysis 5 | Exon or whole-gene deletions 6, 7, 8 |
COL6A2 | 44% | Sequence analysis 4 | Sequence variants |
Duplication/deletion analysis 5 | Exon or whole-gene deletions 7, 8, 9 |
COL6A3 | 18% | Sequence analysis 4 | Sequence variants |
Duplication/deletion analysis 5 | Unknown; none reported 10 |
- 1.
- 2.
Author, personal observation
- 3.
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
- 6.
- 7.
- 8.
Large or whole-gene deletions appear to be rare in collagen VI-related disorders.
- 9.
- 10.
No deletions or duplications involving COL6A3 have been reported to cause collagen type VI-related disorders.
Testing Strategy
To confirm/establish the diagnosis in a proband
Clinical evaluation
Measurement of serum creatine kinase concentration
Muscle MRI for Bethlem myopathy
Note: Muscle MRI is not always done in Ullrich CMD because of the difficulty associated with sedating babies and small children.
Tissue evaluation
Molecular genetic testing of COL6A1, COL6A2, COL6A3
Note: (1) The low variant detection rate is largely attributable to the high degree of genetic heterogeneity in Bethlem myopathy and Ullrich CMD, rather than failure to detect COL6A pathogenic variants; however, deep intronic and cryptic variants are not detectable by sequence analysis. Deletion/duplication analysis does not increase the variant detection frequency greatly, if at all. (2) The recent finding of compound heterozygous pathogenic variants for autosomal recessive forms of collagen type VI-related disorders emphasizes the importance of sequencing the entire coding region of the three genes (COL6A1, COL6A2, COL6A3) to ensure detection of two mutant alleles, when present [Gualandi et al 2009].
Carrier testing for relatives
at risk for autosomal recessive forms of collagen VI-related disorders requires prior identification of the pathogenic variants in the family.
Note: Carriers (heterozygotes) for autosomal recessive forms of collagen type VI-related disorders are not at risk of developing the disorder.
Predictive testing for at-risk asymptomatic adult family members requires prior identification of the pathogenic variants in the family.
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variants in the family.
Clinical Characteristics
Clinical Description
The phenotypes associated with collagen type VI-related disorders, once thought to be distinct entities, were clinically defined long before their molecular basis was discovered. The collagen type VI-related disorders are now recognized to comprise a continuum of overlapping phenotypes with Bethlem myopathy at the mild end, Ullrich congenital muscular dystrophy (CMD) at the severe end, and two less well-defined disorders – autosomal dominant limb-girdle muscular dystrophy and autosomal recessive myosclerosis myopathy – in between. Although these phenotypes are now recognized to overlap and fall on a continuum, these clinical designations are useful for clarification of prognosis and management.
Bethlem Myopathy
The onset of Bethlem myopathy ranges from prenatal to mid-adulthood. Prenatal onset is characterized by decreased fetal movements; neonatal onset with hypotonia or torticollis; early-childhood onset with delayed motor milestones, muscle weakness, and contractures; and adult onset (4th-6th decade) with proximal weakness and Achilles tendon or long finger flexor contractures. As some adults are unaware of weakness, age of onset cannot always be established.
The contractures may come and go during childhood, but nearly all affected individuals eventually exhibit flexion contractures of the fingers, wrists, elbows, and ankles. These contractures can become disabling when combined with muscle weakness.
Individuals can have moderate weakness and atrophy of the muscles of the trunk and limbs with proximal muscles being more involved than distal muscles and extensors more than flexors.
As a result of slow but ongoing progression of the condition, more than two thirds of affected individuals over age 50 years need supportive means (i.e., canes, crutches, or wheelchair) for outdoor mobility [Jöbsis et al 1999, Pepe et al 1999b].
Respiratory muscle and especially diaphragmatic involvement necessitating artificial nocturnal respiratory support is part of the clinical spectrum but is rare and appears to be related to severe weakness occurring in later life [Haq et al 1999]. Respiratory failure may supervene prior to loss of ambulation and may be associated with diaphragmatic weakness [Haq et al 1999].
Cardiac function is usually normal [Mohire et al 1988, de Visser et al 1992].
Ullrich Congenital Muscular Dystrophy (CMD)
In addition to characteristic muscle weakness of early onset, proximal joint contractures, and hyperelasticity of the wrists and ankles, other features observed are congenital hip dislocation, prominent calcanei, and a transient kyphotic deformity at birth.
With time, the distal hyperlaxity can evolve into marked finger flexion contractures and tight Achilles tendons [Furukawa & Toyokura 1977, Muntoni et al 2002].
Some affected children acquire the ability to walk independently; however, progression of the disease often results in later loss of ambulation.
Rigidity of the spine is often associated with scoliosis.
Early and severe respiratory involvement may require artificial ventilatory support in the first or second decade of life.
Failure to thrive is common.
Follicular hyperkeratosis over the extensor surfaces of upper and lower limbs and keloid and cigarette paper scar formation are common.
Cardiac involvement has not been documented to date.
Other Phenotypes
The two additional conditions included in the spectrum of collagen VI myopathies are:
Autosomal dominant limb-girdle muscular dystrophy caused by pathogenic variants in
COL6A1/COL6A2 in three families and
COL6A3 in one family [
Scacheri et al 2002]. Although some
affected individuals had mild weakness with only limited functional impairment, others had a more severe, dystrophic-like weakness with findings including Gower’s maneuver, toe walking, and loss of ambulation. Joint contractures were either absent or much milder than those of typical Bethlem myopathy. Whereas findings of Bethlem myopathy are typically present in infancy, the age at onset in these three families ranged from infancy, to early childhood, to adulthood.
Autosomal recessive myosclerosis myopathy caused by mutation of
COL6A2 in two individuals from one family [
Merlini et al 2008]. Myosclerosis myopathy is characterized by difficulty in walking in early childhood, toe walking, and progressive contractures of calf muscles. In the early 30s the muscles are slender with a firm "woody" consistency and associated with contractures that restrict range of motion of many joints.
Genotype-Phenotype Correlations
In 42 individuals with collagen VI-related myopathy with onset before age two years, biallelic pathogenic variants that caused premature termination codons (associated with autosomal recessive inheritance) were associated with the most severe phenotypes (ambulation never achieved), whereas heterozygous de novo in-frame exon skipping and glycine missense variants (associated with autosomal dominant inheritance) were associated with the moderate-progressive phenotypes (loss of ambulation) [Briñas et al 2010].
In autosomal recessive Ullrich congenital muscular dystrophy (CMD), a large number of pathogenic variants appear to result in premature termination codons with consequent nonsense-mediated mRNA decay. Premature termination codons occur by nonsense variants [Demir et al 2002, Giusti et al 2005, Lampe et al 2005] or frameshift-inducing deletions [Higuchi et al 2001, Giusti et al 2005, Lampe et al 2005], insertions [Camacho Vanegas et al 2001], duplications [Lampe et al 2005], and splice changes [Camacho Vanegas et al 2001, Ishikawa et al 2002]. Splice variants leading to in-frame exon deletions as well as in-frame deletions are other common pathogenic variant types in Ullrich CMD [Demir et al 2002, Ishikawa et al 2004, Baker et al 2005, Lampe et al 2005].
Bethlem myopathy and Ullrich CMD represent a clinical continuum in which individuals presenting with intermediate phenotypes could be considered to have either "mild Ullrich CMD" or "severe Bethlem myopathy." In this context, heterozygous single amino acid substitutions disrupting the Gly-Xaa-Yaa motif of the highly conserved triple helical domain have been described in a milder form of Ullrich CMD [Giusti et al 2005, Lampe et al 2005]. As for Bethlem myopathy, given the high number of variants resulting in benign amino acid changes described for the genes encoding collagen VI subunits, it is difficult to be certain about the pathogenicity of missense variants other than glycine substitutions within the triple helical domain.
In autosomal dominant Ullrich CMD, heterozygous splice site variants leading to in-frame exon deletions and heterozygous in-frame deletions in the coding region share a common motif: they preserve a unique cysteine important for dimer formation, allowing secretion of abnormal tetramers with a consequent dominant-negative effect on microfibrillar assembly [Pan et al 2003, Baker et al 2005].
Penetrance
Parents of individuals with recessively inherited collagen VI-related disorders are usually heterozygous for a COL6A1, COL6A2, or COL6A3 pathogenic variant, but do not appear to manifest any related symptoms.
Individuals with dominantly inherited collagen VI-related disorders are heterozygous for a COL6A1, COL6A2, or COL6A3 pathogenic variant and are symptomatic. However, careful clinical examination may be necessary to identify findings diagnostic of a collagen type VI-related disorder in their minimally symptomatic parents [Peat et al 2007].
Anticipation
Anticipation is not observed.
Prevalence
Prevalence is estimated at 0.77:100,000 in Bethlem myopathy and 0.13:100,000 in Ullrich CMD [Norwood et al 2009]; the disorders are probably currently underdiagnosed.
Both conditions have been described in individuals from a variety of ethnic backgrounds.
Differential Diagnosis
The differential diagnosis of the two major phenotypes observed in the collagen VI-related disorders is discussed below. Of note, a normal to mildly elevated CK, suggestive findings on muscle MRI, and the lack of a cardiac phenotype generally distinguish the collagen type VI-related disorders from these other disorders.
Bethlem myopathy. When contractures are subtle or missed, the major differential diagnoses are the limb-girdle muscular dystrophies (LGMDs) [Scacheri et al 2002].
When contractures are a prominent feature, the major differential diagnoses are X-linked or autosomal dominant Emery-Dreifuss muscular dystrophy, both of which are associated with serious cardiac complications [Pepe et al 2002].
Immunohistochemical testing (i.e., western blotting and immunohistochemistry) performed on muscle biopsy and/or molecular genetic testing can help to establish the diagnosis of some LGMD subtypes such as sarcoglycanopathy, calpainopathy, and dysferlinopathy as well as X-linked or autosomal dominant Emery-Dreifuss muscular dystrophy.
Ullrich congenital muscular dystrophy (CMD). In the neonatal period, the differential diagnosis includes the following:
Other forms of CMD. These do not generally present with the distal hyperlaxity characteristic of Ullrich CMD and are usually associated with serum creatine kinase concentrations higher than those observed in Ullrich CMD. Biochemical testing (i.e., western blotting and immunohistochemistry) performed on the muscle biopsy and
molecular genetic testing can help to establish the diagnosis of some CMD subtypes such as
LAMA2-related muscular dystrophies (MDC1A) or MDC1C (caused by pathogenic variants in
FKRP). In addition, brain MRI may show white matter changes in some CMD subtypes (e.g.,
LAMA2-related muscular dystrophies) and structural abnormalities in others (e.g., Walker-Warburg syndrome, muscle-eye-brain disease, and
Fukuyama congenital muscular dystrophy [FCMD]).
Spinal muscular atrophy (SMA). SMA shows features of denervation rather than myopathic or dystrophic changes on muscle biopsy. It can usually be diagnosed by demonstrating pathogenic variants in
SMN1 or
SMN2.
Rigid spine syndromes. A proportion of rigid spine syndromes are caused by pathogenic variants in
SELENON (
SEPN1) (OMIM
606210), which may overlap with Ullrich CMD later as the
phenotype develops.
Management
Evaluations Following Initial Diagnosis
Bethlem myopathy. To establish the extent of disease and needs of an individual diagnosed with Bethlem myopathy, the following evaluations are recommended:
Evaluation of degree of muscle weakness and mobility
Joint examination for contractures
Physiotherapy assessment and advice regarding stretches/splints for contractures and mobility aids
Possibly orthopedic evaluation if surgery is to be considered for tendon Achilles contractures
Assessment of respiratory status
Seek history of clinical symptoms of nocturnal hypoventilation such as early morning nausea and headaches, daytime somnolence.
Inquire about frequency and severity of chest infections; if any concerns, perform spirometry and nocturnal pulse oximetry.
Ullrich congenital muscular dystrophy (CMD). To establish the extent of disease and needs of an individual diagnosed with Ullrich CMD, the following evaluations are recommended:
Evaluation of degree of muscle weakness and mobility
Examination of back for scoliosis
Joint examination for contractures and hyperlaxity
Physiotherapy assessment and advice regarding stretches/splints for contractures and mobility aids such as swivel walkers and standing frames to achieve upright posture and protect against the development of scoliosis and other contractures
Possibly x-rays of thoracolumbar spine and orthopedic evaluation if scoliosis is clinically suspected
Possibly orthopedic evaluation if hip dislocation is suspected or surgery is to be considered for tendon Achilles contractures
Assessment of respiratory status
Seek history of clinical symptoms of nocturnal hypoventilation such as early morning nausea and headaches, daytime somnolence.
Inquire about frequency and severity of chest infections; if any concerns, perform spirometry and nocturnal pulse oximetry.
Assessment of growth and feeding. Feeding difficulties may manifest as failure to thrive or excessive time taken to finish eating a meal.
Treatment of Manifestations
Bethlem myopathy
Ullrich CMD
Children require active physiotherapy management as soon as the diagnosis is established to promote mobility and independence. Early mobilization in standing frames is important to achieve upright posture and protect against the development of scoliosis and other contractures.
Contractures tend to be aggressive and may require surgery.
Feeding difficulties may manifest as failure to thrive or excessive time taken to finish eating a meal. Consultation with a nutrition specialist may be required to boost calorie intake; for serious problems, feeding by gastrostomy may be the best solution to promote a normal weight gain.
Respiratory support with nocturnal ventilation usually becomes necessary in the first or second decade and can be effective in reducing symptoms, promoting quality of life, and allowing normal schooling [
Wallgren-Pettersson et al 2004].
Scoliosis frequently develops in the first or second decade and requires active management including surgery.
Prevention of Secondary Complications
Prophylaxis of chest infections with vaccination and physiotherapy as well as early and aggressive use of antibiotics may prevent further respiratory problems in both disorders.
Surveillance
Bethlem myopathy
Clinical assessment of muscle weakness, joint contractures, and mobility to inform physiotherapeutic advice regarding stretches/splints and mobility aids
Assessments of respiratory function to detect asymptomatic decline. (Assess clinically by seeking history of clinical symptoms of nocturnal hypoventilation such as early-morning nausea and headaches, daytime somnolence; inquire about frequency and severity of chest infections; if any concerns, perform spirometry and nocturnal pulse oximetry.)
Assessments should be repeated regularly, possibly annually, depending on the clinical status of the individual.
Ullrich CMD
Clinical assessment of muscle weakness, scoliosis, joint contractures, and mobility to inform physiotherapeutic advice regarding stretches/splints and mobility aids
Once scoliosis is evident, regular orthopedic follow up
Assessments of respiratory function to detect asymptomatic decline. (Assess clinically by seeking history of clinical symptoms of nocturnal hypoventilation such as early-morning nausea and headaches, daytime somnolence; inquire about frequency and severity of chest infections; if any concerns, perform spirometry and nocturnal pulse oximetry.)
Clinical assessment of nutritional status
Assessments should be repeated regularly, possibly biannually, depending on the clinical status of the individual.
Pregnancy Management
For a pregnant woman with a collagen VI-related disorder, no specific pregnancy management issues exist; however, prenatal physiotherapy may be indicated.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
make informed medical and personal decisions. The following section deals with genetic
risk assessment and the use of family history and genetic testing to clarify genetic
status for family members; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
Autosomal Dominant Inheritance – Risk to Family Members
Parents of a proband
Sibs of a proband
The risk to the sibs of a
proband depends on the genetic status of the proband's parents.
When the parents are clinically unaffected, the risk to the sibs of a
proband appears to be low, but greater than that of the general population because of possible reduced
penetrance in the parent and/or
germline mosaicism. Although no instances of germline mosaicism have been reported, it remains a possibility.
Offspring of a proband. Each child of an individual with an autosomal dominant collagen VI-related disorder has a 50% chance of inheriting the pathogenic variant.
Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the pathogenic variant identified in the proband and/or is affected, his or her family members may be at risk.
Autosomal Recessive Inheritance
Risk to Family Members
Parents of a proband
Sibs of a proband
At conception, each sib of an
affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic
carrier, and a 25% chance of being neither affected nor a carrier.
Once an at-risk sib is known to be unaffected, the chance of his/her being a
carrier is 2/3.
Offspring of a proband. The offspring of an individual with an autosomal recessive collagen type VI-related disorder are obligate heterozygotes for a pathogenic variant but are themselves unaffected unless they inherit a second pathogenic variant from their other parent.
Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier.
Carrier (Heterozygote) Detection
Carrier testing for family members at risk of being carriers of an autosomal recessive collagen type VI-related disorder is possible if the pathogenic variants have been identified in an affected family member.
Resources
GeneReviews staff has selected the following disease-specific and/or umbrella
support organizations and/or registries for the benefit of individuals with this disorder
and their families. GeneReviews is not responsible for the information provided by other
organizations. For information on selection criteria, click here.
Cure CMD
3217 East Carson Street
Suite 1014
Torrance CA 90712
Phone: 562-444-5656
Email: info@curecmd.org
Muscular Dystrophy Association (MDA) - USA
161 North Clark
Suite 3550
Chicago IL 60601
Phone: 800-572-1717
Email: mda@mdausa.org
Muscular Dystrophy UK
61A Great Suffolk Street
London SE1 0BU
United Kingdom
Phone: 0800 652 6352 (toll-free); 020 7803 4800
Email: info@musculardystrophyuk.org
Congenital Muscle Disease International Registry (CMDIR)
The CMDIR is a patient self-report registry with the goal to register the global congenital muscle disease population including persons with congenital myopathy, congenital muscular dystrophy, and congenital myasthenic syndrome. The CMDIR registers affected individuals of all ages with symptoms from birth through late onset (limb-girdle). Registrants will receive educational information and connections to others in the CMD community, and will be contacted about potential participation in clinical trials for their CMD subtype. 19401 South Vermont Avenue
Suite J100
Torrance CA 90502
Phone: 323-250-2399
Fax: 310-684-2023
Email: counselor@cmdir.org; sarah.foye@cmdir.org
Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
Table A.
Collagen Type VI-Related Disorders: Genes and Databases
View in own window
Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
Molecular Pathogenesis
Collagen VI comprises the three peptide chains α1(VI), α2(VI) (both 140 kd in size), and α3(VI) (260-300 kd in size) [Engvall et al 1986]. The α1(VI) and α2(VI) chains are encoded by the genes COL6A1 and COL6A2, respectively, which are situated head-to-tail on chromosome 21q22.3 [Heiskanen et al 1995] and separated by 150 kb of genomic DNA. COL6A3, the gene encoding the α3(VI) chain, is on chromosome 2q37 [Weil et al 1988].
All three chains contain a central short triple helical domain of 335-336 amino acids with repeating Gly-Xaa-Yaa sequences flanked by large N- and C- terminal globular domains consisting of motifs of approximately 200 amino acids each homologous to von Willebrand factor (vWF) type A domains [Chu et al 1990].
Gene structure
For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants
Given the high number of variants that result in benign amino acid changes described for the three genes encoding the three collagen VI peptide chains, it is difficult to be sure about the pathogenicity of missense variants other than glycine substitutions within the triple helical domain.
Normal gene product. Extracellular matrix molecules are critical for skeletal muscle stability, regeneration, and muscle cell matrix adhesion [Helbling-Leclerc et al 1995, Sewry & Muntoni 1999, Emery 2002]. Collagen VI is a ubiquitous extracellular matrix protein [von der Mark et al 1984] that forms a microfibrillar network in close association with the basement membrane around muscle cells and interacts with several other matrix constituents [Burg et al 1996, Kuo et al 1997, Wiberg et al 2003].
The assembly of collagen VI is a complex multistep process. Association of the three genetically distinct subunits α1(VI), α2(VI), and α3(VI) to form a triple helical monomer is followed by staggered assembly into disulfide-bonded antiparallel dimers, which then align to form tetramers, also stabilized by disulfide bonds. Outside of the cell, tetramers, the secreted form of collagen VI, associate end to end to form the characteristic beaded microfibrils [Furthmayr et al 1983, Engvall et al 1986, Lamandé et al 1998].
Abnormal gene product
Autosomal dominant collagen type VI-related disorders. Heterozygous single amino acid substitutions disrupting the Gly-Xaa-Yaa motif of the highly conserved triple helical
domain of any of the three
COL6A genes [
Jöbsis et al 1996,
Pepe et al 1999a,
Scacheri et al 2002,
Lampe et al 2005,
Lucioli et al 2005], depending on their location, appear to either interfere with intracellular chain assembly or, following successful secretion, cause kinking of the tetramers, thus affecting extracellular microfibril formation [
Lamandé et al 2002]. Functional
haploinsufficiency via a
dominant-negative effect has also been reported as the pathogenic mechanism for some
missense and
splice site variants [
Lamandé et al 1999]. Heterozygous splice site variants (associated with
autosomal dominant disease) leading to
in-frame exon deletions as well as in-frame
genomic deletions preserve a unique cysteine important for dimer formation, allowing secretion of abnormal tetramers with a consequent dominant-negative effect on microfibrillar assembly [
Pan et al 2003,
Baker et al 2005].
Autosomal recessive collagen type VI-related disorders. Most variants associated with
autosomal recessive disease reported to date are protein-truncating
nonsense variants. Some have been shown to result in absence of collagen VI because of nonsense-mediated
mRNA decay [
Zhang et al 2002].
Chapter Notes
Revision History
9 August 2012 (me) Comprehensive update posted live
6 April 2007 (me) Comprehensive update posted live
25 June 2004 (me) Review posted live
18 February 2004 (kf) Original submission