The present study identified a novel heterozygous c.3517G > A mutation (Gly1173Ser) in the COL2A1 gene in a large Chinese family. The main clinical characteristics of the affected patients include ANFH and premature hip osteoarthritis, which has been described by the previous studies[10, 11]. In recent decades, > 200 mutations have been identified in the COL2A1 gene, including single substitution, splice-site mutations, insertions and deletions[1]. COL2A1 mutations have been associated with various human disorders, which are collectively termed type II collagenopathies[14, 15].
Until now, only six different COL2A1 mutations have been identified in patients with ANFH. As Table 1 shows, five of the six mutations are glycine to serine substitutions in the Gly-X-Y triple-helix, and Gly1170Ser is the hot spot, which has been identified in four families with ANFH.
Table 1
COL2A1 mutations have been identified in patients with ANFH
Protein
|
cDNA
|
Region
|
Race
|
References
|
Gly582Ser
|
c.1744G > A
|
Gly-X-Y
|
Japanese
|
Kishiya et al. 2014
|
Gly630Ser
|
c.1888G > A
|
Gly-X-Y
|
Chinese
|
Li et al. 2014
|
Gly717Ser
|
c.2149G > A
|
Gly-X-Y
|
Chinese
|
Liu et al. 2005
|
Gly1170Ser
|
c.3508G > A
|
Gly-X-Y
|
Chinese
|
Liu et al. 2005; Su et al. 2008; Wang et al. 2014; Liu et al. 2018
|
Gly1173Ser
|
c.3517G > A
|
Gly-X-Y
|
Chinese
|
The present study
|
Thr1383Met
|
c.4148G > A
|
C-propeptide
|
Unknown
|
Kannu et al. 2011
|
The variants shown are described using the NM_001844.4 transcript reference sequence.
|
Table 2
Characteristics of the family members
|
Sex
|
Age
|
Disease condition
|
Age of onset
|
Height
|
Genotype
|
III1
|
F
|
73
|
Not affected
|
/
|
166
|
G/G
|
IV1
|
M
|
49
|
affected
|
36
|
161
|
G/A
|
IV2
|
M
|
51
|
affected
|
30
|
160
|
G/A
|
IV3
|
M
|
48
|
affected
|
25
|
163
|
G/A
|
IV4
|
F
|
58
|
Not affected
|
/
|
156
|
G/G
|
IV5
|
F
|
52
|
affected
|
40
|
155
|
G/A
|
IV6
|
M
|
49
|
Not affected
|
/
|
180
|
G/G
|
IV7
|
M
|
62
|
affected
|
40
|
163
|
G/A
|
IV8
|
M
|
53
|
Not affected
|
/
|
165
|
G/G
|
IV9
|
F
|
51
|
affected
|
38
|
157
|
G/A
|
IV10
|
F
|
49
|
affected
|
20
|
155
|
G/A
|
IV11
|
M
|
52
|
affected
|
40
|
158
|
G/A
|
IV12
|
M
|
50
|
affected
|
19
|
160
|
G/A
|
IV13
|
M
|
50
|
Not affected
|
/
|
172
|
G/G
|
IV14
|
F
|
48
|
Not affected
|
/
|
165
|
G/G
|
V1
|
F
|
25
|
Not affected
|
/
|
167
|
G/G
|
V2
|
F
|
35
|
affected
|
26
|
156
|
G/A
|
V3
|
F
|
34
|
Not affected
|
/
|
159
|
G/G
|
V4
|
M
|
27
|
Not affected
|
/
|
165
|
G/G
|
The nature of the mutations and their localizations in the protein seem to explain the phenotypic differences, at least to a certain extent[15]. Truncating mutations leading to reduced amounts of normal type II collagen are related with mild phenotypes. In contrast, missense mutations, which replace one Gly residue in the Gly-X-Y repeating pattern, are usually related with severe phenotypes. The Gly-X-Y triple-helix motif is crucial for the proper crosslinking of the pro-α1 peptide chain to form functional type II collagen. Mortier et al. reported that there are numerous excessive post‑translational modifications in type II collagen in patients carrying a Gly-substituted mutation[16].
The exception is glycine to serine substitutions. Glycine to serine substitutions, unlike glycine to nonserine residue substitutions, produced variable phenotypes, with both inter- and intra-familial phenotypic variation[17, 18]. In type I collagenopathies, the severity of the disease has been correlated with the size and charge of the substituted amino acid, specifically Ala < Ser < Cys < Arg < Glu < Asp < Val, in order from least to most disruptive[19]. The same domain-specific effect may exist in type II collagenopathies. Sobetzko et al. identified c.3517G > C mutation leading to Gly1173Arg in COL2A1 in a boy affected with a severe form of spondyloepiphyseal dysplasia[20]. The mutation position is exactly the same with the present study. However, glycine to arginine substitutions usually causes severe phenotypes.
Although most mutations associated with ANFH are glycine to serine substitutions in the Gly-X-Y triple-helix, there is one exception: c.4148G > A (Thr1383Met) in the C-propeptide of COL2A1 gene[12]. C-propeptide mutations typically cause spondyloperipheral dysplasia, characterized by vertebral body abnormalities, hip dysplasia and brachydactyly type E. Therefore, more cases need to be described and more mutations needs to be identified, to clarify the genotype-phenotype relationship.
In summary, we identified a novel heterozygous c.3517G > A mutation (Gly1173Ser) in the Gly-X-Y triple-helix motif of COL2A1 in a large Chinese family with ANFH. Our findings will provide clues to the phenotype-genotype relations and may assist not only in the clinical diagnosis of familial ANFH but also in the interpretation of genetic information used for prenatal diagnosis and genetic counseling.