Homozygous Inactivating Mutations in the NKX3-2 Gene Result in Spondylo-Megaepiphyseal-Metaphyseal Dysplasia

Abstract

Spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD) is a rare skeletal dysplasia with only a few cases reported in the literature. Affected individuals have a disproportionate short stature with a short and stiff neck and trunk. The limbs appear relatively long and may show flexion contractures of the distal joints. The most remarkable radiographic features are the delayed and impaired ossification of the vertebral bodies as well as the presence of large epiphyseal ossification centers and wide growth plates in the long tubular bones. Numerous pseudoepiphyses of the short tubular bones in hands and feet are another remarkable feature of the disorder. Genome wide homozygosity mapping followed by a candidate gene approach resulted in the elucidation of the genetic cause in three new consanguineous families with SMMD. Each proband was homozygous for a different inactivating mutation in NKX3-2, a homeobox-containing gene located on chromosome 4p15.33. Striking similarities were found when comparing the vertebral ossification defects in SMMD patients with those observed in the Nkx3-2 null mice. Distinguishing features were the asplenia found in the mutant mice and the radiographic abnormalities in the limbs only observed in SMMD patients. The absence of the latter anomalies in the murine model may be due to the perinatal death of the affected animals. This study illustrates that NKX3-2 plays an important role in endochondral ossification of both the axial and appendicular skeleton in humans. In addition, it defines SMMD as yet another skeletal dysplasia with autosomal-recessive inheritance and a distinct phenotype.

Transcriptional control of chondrocyte specification and differentiation

“…NKX3.2/BAPX1 is an important transcriptional repressor in chondrogenesis [111]. Its nullizygosity in humans causes spondylo-megaepiphyseal-metaphyseal dysplasia, i.e., short trunk and GP and ossification defects in the axial and appendicular skeleton [112]. Induced by SHH and maintained by bone morphogenetic protein (BMP) signaling in SSCs, NKX3.2 promotes chondrogenesis by inducing Sox9 upregulation and repressing Runx2 [113].…”

The chondrocytic journey in endochondral bone growth and skeletal dysplasia

“…Nkx3 .2‐null mice die perinatally, with a more severe vertebral phenotype than that of the appendicular bones (Lettice et al, ; Tribioli and Lufkin, ; Akazawa et al, ). Homozygous inactivating mutations in human NKX3.2 result in the rare skeletal dysplasia spondylo‐megaepiphyseal‐metaphyseal dysplasia (Hellemans et al, ), with symptoms resembling those of Nkx3.2 ‐null mice, indicating NKX3.2 plays a more dominant role in controlling chondrogenesis in the axial skeleton.…”

The role of Nkx3.2 in chondrogenesis

“…In humans, the recessive mutation of Nkx3.2 results in spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD) (Hellemans et al, 2009; Simon et al, 2012). This rare condition manifests with cervical spine deformation, spinal cord injury, and shorter stature; individuals with SMMD possess short, stiff necks and trunks, along with disproportionate limbs, fingers, and toes.…”

“…This rare condition manifests with cervical spine deformation, spinal cord injury, and shorter stature; individuals with SMMD possess short, stiff necks and trunks, along with disproportionate limbs, fingers, and toes. While many of these symptoms resemble Nkx3.2 mouse mutants when compared with Nkx3.2 knockout mouse, a number of differences are present (Hellemans et al, 2009). Unlike patients with SMMD, dysplasia of the appendicular skeleton is not observed in the Nkx3.2 knockout mouse.…”