Jobard et al. (2003) undertook a genome-wide scan, using 400 polymorphic microsatellite markers in an Algerian family with three members affected with Kindler syndrome, and identified a 7 cM region on chromosome 20 to co-segregate with the disease. Further refining of the region using three additional affected families, two from Algeria, and one from Tunisia, narrowed the interval down to an 834 kb interval, flanked by the markers D20S905 and D20S192. Jobard et al. (2003) considered nine genes within this interval, and finally identified mutations in the C20orf42 gene in the patients, and proceeded to give it the name Kindlerin. Expression analysis and protein sequencing revealed the presence of several domains within the Kinderlin gene, including a FERM domain, an NPKY sequence motif, and a Pleckstrin Homology (PH) domain. Two different mutations in the Kindlerin gene were identified in two of the Algerian families. These included a splice site mutation (385+2T>C) in exon 3 in all 3 patients from the first family, and 464delA in exon 4 in both affected siblings in another family. Both these mutations were expected to lead to protein truncation and loss of the FERM and PH (Pleckstrin homology) domain. These patients also had a homozygous Alu insertion in intron 14. No mutation could be identified in one other Algerian patient, although he shared clinical features with the other patients and had a homozygous interval of 2.6 Mb on chromosome 20p12.3. The authors proposed that kindlerin might be involved in the bidirectional signaling between integrin molecules in the membrane and the cytoskeleton, and could be involved in cell adhesion processes via integrin signaling [See also: Tunisia > Jobard et al., 2003].

Siegel et al. (2003) identified the nonsense mutation 193C>T in exon 3 of the KIND1 gene, predicting amino acid change Q65X, in a consanguineous Jordanian family with two siblings affected with Kindler syndrome. [See also: Oman > Siegel et al., 2003].

In an attempt to identify the genetic basis of Kindler syndrome, Siegel et al. (2003) confirmed the location of the locus identified by Jobard et al. (2003) in the Panamanian families and in individuals with Kindler syndrome from diverse geographic backgrounds, some of whom had previously been described (Al Aboud et al., 2002). Siegel et al. (2003) studied affected and healthy members from 24 families, including consanguineous families from Oman, Jordan, Saudi Arabia, and other countries. Linkage analysis in these consanguineous families showed homozygosity across the same region, leading to a maximum multipoint LOD score of 11.7 at theta=0 with D20S905. Six genes within the critical interval between D20S95 and D20S192 were sequenced. But, mutations were detected in only one of the six genes: FLJ20116, which was renamed as KIND1. The Omani family with two affected siblings was shown to have the 811C>T mutation in exon 6 of the KIND1 gene, predicting the amino acid change R271X.

A new mutation in the KIND1 gene was identified in a study carried out by Ashton et al. (2004) along with demonstrating the importance of carboxy-terminal antikindlin-1 antibody in diagnosing Kindler syndrome (KS). Two female Omani patients (7 and 19-yrs old) from unrelated consanguineous families, presented with trauma induced blistering in childhood, photosensitivity, and poikiloderma, and were diagnosed with KS. One patient had dysphagia and esophageal stenosis as well, and had a sibling who died in early infancy because of skin fragility and secondary infection. Mutation of the KIND1 gene of the patients was identified by PCR amplification of the DNA, sequenced using ABI 310 genetic analyzer, and then confirmed by restriction endonuclease digestion. The KIND1 gene was found to have a homozygous G1848A substitution in exon 14 (W616X). Haplotype analysis of the patient's DNA when compared to that of controls', showed that the W616X mutation occurred in both patients on a similar genetic background, consistent with the propagation of an ancestral allele in the Omani gene pool. Ashton et al. (2004) suggested using this phenomena in mutation detection in patients of the same ethnic group. Immunofluorescence labeling with antikindlin 1 antibody in the patients showed complete absence of fluorescence. Ashton et al. (2004) emphasized the usefulness of this antibody as a diagnostic probe in KS.

In the study conducted by Siegel et al. (2003) to identify the genetic basis of Kindler Sydrome, at least one consanguineous family from Saudi Arabia was analyzed. In this family, the disease was linked to mutations in the KIND1 gene [See also: Oman > Siegel et al., 2003]

Jobard et al. (2003) included a Tunisian family with affected members in their study to identify the gene responsible for Kindler syndrome. Both patients from the family were found to carry a 1714insA mutation in exon 13 of the Kindlerin gene, which was predicted to lead to a stop codon, and cause protein truncation in the PH domain [See also: Algeria > Jobard et al., 2003].