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Table 1 Genetic and molecular findings in human aggrecanopathies and naturally occurring animal models

From: The aggrecanopathies; an evolving phenotypic spectrum of human genetic skeletal diseases

Gene mutation

Exon

Protein change

Domain

Molecular mechanism

Phenotype

Reference

c.272delA

3

Arg93Alafs*41

G1

Presumed haploinsufficiency

Idiopathic short stature

[15]

c.2026 + 1G > A

10

Not determined (but presumed exon skip)

G2

1.Presumed truncated protein

Idiopathic short stature

[15]

2. Possible disruption to trafficking

c.3986dupC

12

Gly1330Trpfs*221

CS1

Presumed haploinsufficiency

SED Kimberley type

[13]

c.5391delG

12

Gly1797Glyfs*52

CS2

Presumed haploinsufficiency

Dominant idiopathic short stature

[22]

c.7064 T > C

14

Leu2355Pro

G3

Presumed neomorphic

Short stature, accelerated bone maturation, and early growth cessation

[15]

c.6799G > A

15

Asp2267Asn

G3

Presumed neomorphic

Recessive SEMD, aggrecan type

[12]

c.7249G > A

16

Val2303Met

G3

Presumed neomorphic

Dominant osteochondritis dissecans, short stature, and early-onset osteoarthritis

[14, 17]

BD1 allele: 2266_2267insGGCA

11

Frame shift and introduction of PTC in exon 11 (amino acid position 914)

 

1. Null due to NMD of mRNA from mutant allele

Bulldog dwarfism (Dexter Cattle)

[11]

Homozygous animals are embryonically lethal; heterozygous animals have short-limbed dwarfism with variable penetrance

2. Functional null due to production of truncated protein

BD2 allele: −198C > T

1

Introduction of a novel start codon and translation of a 91 amino acid peptide with no resemblance to aggrecan; introduction of a PTC

n/a

7 bp deletion leading to a PTC in exon 6.

5

Reduced mRNA levels in cmd/cmd (41 %) and cmd/wt (81 %) mice; truncated aggrecan molecule

G1

Functional and/or transcriptional null allele

Cmd (mouse)

[2429]

Homozygous mice are perinatally lethal; heterozygous mice show age-related spinal degeneration

Large deletion

2–18

Unknown

G1-G3

Presumed null allele

Cmd-bc (mouse)

[30]

Homozygous mice are perinatally lethal

Glu1513Ter

10

Truncated aggrecan precursor that is retained in the ER; reduced mRNA levels

CS2

Presumed null allele

Nanomelia (chicken)

[9, 27, 29, 31, 33]

Homozygous chicks are embryonically lethal with shortened and malformed limbs

Unknown

n/a

Unknown

Unknown

Unknown

CCI (rat)

[35]

Homozygous rats have short-limbed dwarfism, delayed anterior fontanel closing and insufficient cartilage calcification

  1. Details of the five aggrecan mutations that have been identified in families with a diverse range of human skeletal dysplasia and the naturally occurring animal models that have previously been studied
  2. Key: NMD nonsense mediated degradation, PTC premature termination codon, G1 globular domain, G2 globular domain, CS chondroitin sulphate attachment domain, SED spondyloepiphyseal dysplasia, SEMD spondyloepimetaphyseal dysplasia, BD bull dog dwarfism, cmd cartilage matrix deficiency allele/mouse, wt wild type allele
  3. *Indicates at which position the new reading frame encounters a translation termination (stop) codon stop