Strong founder effect for a transglutaminase 1 gene mutation in lamellar ichthyosis and congenital ichthyosiform erythroderma from Norway

Abstract

Autosomal recessive congenital ichthyosis (ARCI) is a clinically heterogeneous disorder of keratinisation. It was recently shown that mutations in the transglutaminase 1 (TGM1) gene may be associated with the clinical subtypes lamellar ichthyosis (LI) and non-bullous congenital ichthyosiform erythroderma (CIE). Thirty-six Norwegian families with LI and seven with non-bullous CIE were studied with microsatellite markers linked to the TGMI gene. One common haplotype for two markers was found on 74% of disease associated chromosomes. Three individuals homozygous for the common haplotype, two affected by LI and one affected by CIE, were analysed for mutations in the TGM1 gene. All three patients were found homozygous for a single A to G transition located in the canonical splice acceptor site of intron 5. Probands from the remaining 40 families with LI and CIE were screened for this mutation and the A to G transition was found on 61 out of 72 alleles associated with LI and on 9 out of 15 alleles associated with CIE. These findings suggest a single founder mutation for the majority of patients with LI and CIE in Norway. The 2526A-->G mutation results in the insertion of a guanosine at position 877 (876insG) in the mature cDNA and the frame shift creates a premature termination at codon 293. The mutation was previously observed in one family with a resulting cDNA that included the entire intron 5. These results suggest that the mutation can result in variant transcripts in different individuals.

Spectrum of Autosomal Recessive Congenital Ichthyosis in Scandinavia: Clinical Characteristics and Novel and Recurrent Mutations in 132 Patients

“…The point mutation c.877-2A>G was identified in 14% of alleles associated with LI/CIE, mainly in the Swedish patients. This mutation has also been described from several other countries (37,38,40,41,(48)(49)(50)(51)(52)(53) and is reported as a founder mutation in Norway (49), located close to Sweden. The p.Ser358Arg mutation was originally identified in a Swedish family (28) and there is no report of this mutation outside Sweden and Norway (unpublished data), which suggests a local founder mutation.…”

Clinical and morphological correlations for transglutaminase 1 gene mutations in autosomal recessive congenital ichthyosis

“…Similar kinds of result were also seen in the study of 43 Norwegian ARCI families where one major founder mutation A2526G (corresponding to our mutation 3349 A to G) was found in patients with both type I and type II. 16 Interestingly, this mutation was found only in one Finnish compound heterozygote patient whose clinical picture was quite untypical compared with other TGM 1 mutation carriers (Figure 3c). …”

“…11 After our previous studies one additional mutation, 3349A to G, was found in restriction enzyme Msp I analysis of 27 families as described earlier. 16 …”

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

“…160 The ultrastructural features of the so-called EM classification described by the Heidelberg group are based on a glutaraldehyde fixation of the skin biopsy specimen. [206][207][208][209][210] With this technique polygonal clefts in the SC can be observed as an ultrastructural key feature of TGase-1 deficiency, 211 aberrant vesicular structures may indicate NIPAL4 (;ICHTHYIN ) mutations in ARCI, 33 and trilamellar membrane aggregations in the SC and SG (EM type IV) are pathognomonic for ichthyosis prematurity syndrome. 89 Detachment of the SC from the SG with asymmetric cleavage of corneodesmosomes is a specific feature of NS.…”