Ullrich Congenital Muscular Dystrophy 2

A number sign (#) is used with this entry because of evidence that Ullrich congenital muscular dystrophy-2 (UCMD2) is caused by homozygous mutation in the COL12A1 gene (120320) on chromosome 6q. One such family has been reported.

For a discussion of genetic heterogeneity of Ullrich congenital muscular dystrophy, see UCMD1 (254090).

Clinical Features

Zou et al. (2014) reported 2 brothers, born to consanguineous Turkish parents, with features suggesting Ullrich congenital muscular dystrophy. The older brother was profoundly weak at birth, with strikingly hypermobile distal joints, moderate and more proximal joint contractures, and kyphoscoliosis. He also had mild facial weakness, a high-arched palate, and absent deep tendon reflexes. He required noninvasive nighttime ventilation before 3 years of age. Motor development was severely delayed, and he required a power wheelchair for mobility. Progressive scoliosis developed, requiring spinal fixation surgery at age 9. His younger brother had similar findings at birth, presenting with a combination of weakness with significant distal hyperlaxity and milder proximal contractures. He was unable to stand or walk. Creatine kinase values and nerve conduction velocities were normal in both boys. Muscle biopsy in the older brother showed variability in fiber diameter but no evidence of active degeneration or regeneraion. Both parents reported a history of delayed gross motor development, with achievement of ambulation after the age of 2 years. Zou et al. (2014) noted differences from UCMD1: the joint hypermobility in their patients was more pronounced and widespread, and the respiratory insufficiency in the older brother was earlier than expected in UCMD1.

Inheritance

The transmission pattern of UCMD2 in the family reported by Zou et al. (2014) was consistent with autosomal recessive inheritance.

Mapping

By homozygosity mapping in a Turkish family segregating UCMD2, Zou et al. (2014) found a region of homozygosity on chromosome 6 between SNPs rs1158058 and rs1665914 that contained the candidate gene COL12A1.

Molecular Genetics

By mutation analysis on dermal fibroblast-derived cDNA from 2 brothers with UCMD2, Zou et al. (2014) identified homozygosity for a splice site mutation in the COL12A1 gene (120320.0001). The parents were carriers of the mutation, which was not present in the dbSNP or 1000 Genomes Project databases. Patient muscle and cultured fibroblasts showed absent extracellular immunostaining for type XII collagen. Extracellular immunostaining for type VI collagen and laminin-gamma-1 (LAMC1; 150290) was preserved.

Animal Model

Izu et al. (2011) generated Col12a1-null mice by targeted deletion of exons 2-5. The knockout mice had fragile bones with a disorganized collagen fiber arrangement, decreased expression of bone matrix proteins, and decreased bone-forming activity associated with delayed terminal differentiation. Zou et al. (2014) showed that the knockout mice had decreased grip strength, a delay in fiber-type transition, and a deficiency in passive force generation, while the muscle seemed more resistant to eccentric contraction-induced force drop, indicating a role for a matrix-based passive force-transducing elastic element in the generation of the weakness.