Localisation of the gene for a dominant congenital spinal muscular atrophy predominantly affecting the lower limbs to chromosome 12q23–q24

Abstract

Spinal muscular atrophies are a heterogeneous group of disorders. They differ in time of onset, clinical presentation, progression, severity and mode of inheritance. In 1985 a Dutch family was described with a dominant, nonprogressive spinal muscular atrophy presenting at birth with arthrogryposis (MIM 600175). Linkage analysis was performed in this family. After having excluded the loci for Werdnig-Hoffmann's disease and for dominant distal spinal muscular atrophy with upper limb predominance, we were able to localise the gene to a 10 cM interval between the markers D12S78 and D12S1646 on chromosome 12q23-q24. Recently, dominant scapuloperoneal spinal muscular atrophy has been localised to an overlapping interval. However, the clinical appearances of scapuloperoneal spinal muscular atrophy and the present disorder make allelism unlikely. In 1994, a second Dutch family with a disorder similar to the present one was described. We excluded linkage to markers of the 12q23-q24 region in this family and thereby proved genetic heterogeneity of this type of dominant, congenital and nonprogressive spinal muscular atrophy.

Dominant spinal muscular atrophy with lower extremity predominance

“…Lower extremity predominance has been described in several other dominant SMA families, [25][26][27] including the one family with a mutation in TRPV4 on 12q23-q24. 15,16,28,29 However, in contrast to SMA-LED, these pedigrees showed more prominent distal leg weakness, high rates of arthrogryposis, and congenital onset. Although the features of SMA-LED are different from most other autosomal dominant SMAs, we cannot exclude the possibility that SMA-LED represents one end of a spectrum shared with these other families.…”

PFM1 (PRDM4), a New Member of the PR-Domain Family, Maps to a Tumor Suppressor Locus on Human Chromosome 12q23–q24.1

“…Gene deletion or loss of heterozygosity in this region is found in several types of human cancers including ovarian cancer (6,24), pancreatic cancer (14), and gastric cancers (25). In addition, a gene involved in spinal muscular atrophies is thought to reside on 12q23-q24.1, which remains to be cloned (27). Together with the known involvement of the PR-domain family in cell differentiation and cancer, the chromosomal location of PFM1 suggests an important role for PFM1 in human cancer.…”

CMT2C with vocal cord paresis associated with short stature and mutations in the TRPV4 gene

“…This category was subsequently confirmed and linked to chromosome 12q23-24. [5][6][7][8] Recently a few groups have described several families with autosomal dominant CMT2C, scapuloperoneal spinal muscular atrophy (SPSMA), and congenital distal spinal muscular atrophy (SMA) having mutations in the calcium permeable ion channel gene (transient receptor potential cation channel, subfamily V, member 4; TRPV4). [9][10][11][12] Independently, 2 groups previously reported other mutations in the TRPV4 gene associated with the bone disorders spondylometaphyseal dysplasia, metatropic dysplasia, and brachyolmia 13,14 (recently further expanded 15 ).…”