Genetic heterogeneity in type III familial cutaneous syndactyly and linkage to chromosome 7q36

Abstract

The ZRS (zone of polarizing activity regulatory sequence) is a long-range limb-specific Sonic Hedgehog (SHH) enhancer. In humans, the ZRS is located in chromosome 7q36 within intron 5 of LMBR1; approximately 1 Mb telomeric of SHH. Point mutations and duplications of the ZRS lead to a variable phenotype of preaxial polydactyly/triphalangeal thumb, tibial hypoplasia, radial ray deficiency, and type IV familial syndactyly (syndactyly of all digits with polydactyly). The ZRS is conserved among mammals and fish and regulates the expression of SHH. In mice, the conserved ZRS within the Lmbr1 gene is found in chromosome 5. The Hammertoe (Hm) mouse mutants have a mutation in the Lmbr1 locus and show syndactyly of digits 2-5 without polydactyly. No previous reports have described isolated syndactyly without polydactyly to be related to the LMBR1 locus in humans. In this report, we describe a family with simple cutaneous syndactyly involving digits 2-5, without polydactyly which is consistent with the phenotype of type III syndactyly. The locus we identified on ch7q36.3 is syntenic to the Hm locus; and affected members of the family had a phenotype analogous to Hm. Hence, the type of syndactyly described in the current report may be equivalent to Hm mice.

A familial case of Syndactyly type IV due to a novel duplication of ~222.23 kb covering exons 2-17 of the LMBR1 gene: a case report

“…The ZRS locates approximately 1 Mb away from SHH (Lettice et al, 2003), which controls the expression of SHH in the developing limb, and is conserved among mammals and fish (Lettice et al, 2003). The Lmbr1 mutant mouse displayed syndactyly involving digits II to V (Al-Qattan, Shamseldin, Al Mazyad, Al Deghaither, & Alkuraya, 2013), which is in line with the phenotypes of SD4.…”

A novel mutation (g.106737G>T) in zone of polarizing activity regulatory sequence (ZRS) causes variable limb phenotypes in Werner mesomelia

“…Heterogenous point mutations and duplications in this region result in overlapping phenotypes affecting the hands and feet [Lettice et al, ; Gurnett et al, ; Furniss et al, ; Klopocki et al, ; Sun et al, ; Semerci et al, ; Farooq et al, ; Wieczorek et al, ; Albuisson et al, ; Al‐Qattan et al, ; Laurell et al, ; VanderMeer et al, ; Cho et al, ]. There are other reports on hand phenotypes (familial cutaneous syndactyly and preaxial polydactyly) that map to this region but no mutations have been reported [Li et al, ; Al‐Qattan et al, ]. The variety of mutations and phenotypes probably highlight the complex interaction of ZRS and other regulatory elements in limb development through SHH [Lettice et al, 2008, ].…”

Advances in the Molecular Genetics of Non-syndromic Syndactyly

“…SD4 and triphalangeal thumb-polysyndactyly syndrome (TPTPS) are genetically homogeneous and are considered as a continuum of phenotypes [ 50 ]. Both entities are autosomal dominant and are caused by mutations in the zone of polarizing activity regulatory sequence (ZRS) located in chromosome 7q36 within intron 5 of the LMBR1 gene [ 51 ]. In 2007, SD4 disease gene locus was suggested to be on chromosome 7q36 by linkage and haplotype analysis of a Chinese family, with the maximum two-point LOD score of 1.613 [ 52 ].…”

“…In 2013, 115.3 kb duplication of the ZRS was detected in a family with SD4 and TPTPS [ 50 ]. The ZRS locates approximately 1 Mb away from SHH [ 50 ], and is conserved among mammals and fish [ 51 ].…”

“…The mouse with Shh turned-off in the distal mesenchyme of the limb at later stages of limb bud development showed syndactyly [ 55 ]. The Hammertoe ( Hm ) mutant mouse has a mutation in the Lmbr1 gene [ 51 ]. The Lmbr1 Hm/+ and Lmbr1 Hm/Hm mice displayed syndactyly involving digits II to V [ 51 ].…”