COL10A1 – Schmid metaphyseal chondrodysplasia

COL10A1 encodes the alpha-1 chain of type X collagen, a homotrimeric extracellular matrix protein expressed by hypertrophic chondrocytes in the growth plate. Heterozygous mutations in COL10A1 cause Schmid metaphyseal chondrodysplasia (SMCD), an autosomal dominant skeletal dysplasia characterized by short stature, coxa vara, genu varum, and waddling gait. The evidence base includes multiple unrelated families and functional assays delineating the pathogenic mechanism. This summary evaluates the clinical validity using ClinGen criteria and integrates genetic and experimental data to guide diagnosis and management.

Clinical Validity

The association of COL10A1 with SMCD is Definitive. Over 30 probands from at least 15 unrelated autosomal dominant families have been reported, each carrying heterozygous COL10A1 variants that segregate with disease ([PMID:8004099]; [PMID:15880705]). Functional concordance across decades of studies confirms a consistent molecular mechanism, and no significant conflicting evidence has been reported.

Genetic Evidence

SMCD is inherited in an autosomal dominant manner. Segregation analyses have documented at least 15 affected relatives with co-segregating COL10A1 variants ([PMID:8004099]). To date, more than 33 distinct pathogenic variants have been identified, including missense substitutions, frameshift insertions/deletions, and nonsense mutations predominantly clustering in the C-terminal NC1 trimerization domain. For example, c.1853G>T (p.Gly618Val) impairs NC1-mediated assembly ([PMID:7876225]). Recurrent mutations such as 1992delCT have arisen independently in multiple lineages, indicating a mutational hotspot ([PMID:8996971]).

Variant Spectrum and Phenotypic Spectrum

Most SMCD variants lie in exon 3 encoding the NC1 domain, disrupting trimer formation by altering key glycine, tyrosine, or proline residues. Variant types include 18 missense (e.g., c.1853G>T (p.Gly618Val)), 10 frameshifts (e.g., c.1992_1993delCT (p.Leu665Ter)), and 5 nonsense mutations (e.g., c.1896C>A (p.Tyr632Ter)). Phenotypically, heterozygotes uniformly exhibit metaphyseal dysplasia, short stature (HP:0004322), coxa vara (HP:0002812), genu varum (HP:0002970), and waddling gait (HP:0002515).

Functional Evidence

In vitro expression and trimer assembly assays demonstrate that NC1 missense and truncating mutations prevent collagen X multimer formation without dominant interference of the wild‐type chains ([PMID:8662807]). Cartilage analyses confirm nonsense-mediated mRNA decay and haploinsufficiency for PTC alleles ([PMID:9525992]). Mouse models harboring Col10a1 NC1 mutations recapitulate the expanded hypertrophic zone, ER stress, and unfolded protein response observed in patient cartilage, indicating both haploinsufficiency and potential dominant-negative effects ([PMID:17403716]).

Integration and Take-Home

The definitive gene–disease relationship and clear molecular mechanism support the use of COL10A1 sequencing for diagnosis and family screening of SMCD. Knowledge of hotspot regions facilitates targeted testing, and functional understanding opens avenues for therapeutic modulation of ER stress. Key take-home: COL10A1 NC1 domain mutations cause SMCD via impaired trimer assembly and haploinsufficiency, justifying genetic testing for early diagnosis and management.

References

• Human molecular genetics • 1994 • Additional mutations of type X collagen confirm COL10A1 as the Schmid metaphyseal chondrodysplasia locus PMID:8004099
• The Journal of biological chemistry • 1995 • Type X collagen multimer assembly in vitro is prevented by a Gly618 to Val mutation in the alpha 1(X) NC1 domain resulting in Schmid metaphyseal chondrodysplasia PMID:7876225
• The Japanese journal of human genetics • 1996 • A recurrent 1992delCT mutation of the type X collagen gene in a Japanese patient with Schmid metaphyseal chondrodysplasia PMID:8996971
• Biochemical and molecular medicine • 1996 • Dideoxyfingerprinting (ddF) analysis of the type X collagen gene (COL10A1) and identification of a novel mutation (S671P) in a kindred with Schmid metaphyseal chondrodysplasia PMID:8986632
• Human mutation • 2005 • Mutations of COL10A1 in Schmid metaphyseal chondrodysplasia PMID:15880705
• The Journal of biological chemistry • 1996 • Site-directed mutagenesis of human type X collagen. Expression of alpha1(X) NC1, NC2, and helical mutations in vitro and in transfected cells PMID:8662807

Evidence Based Scoring (AI generated)