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Two pathogenic mutations located within the 5'-regulatory sequence of the GJB1 gene affecting initiation of transcription and translation

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Kabzińska D., Kotruchow K., Ryniewicz B., Kochański A.

2011

vol. 58

issue 3

359-363

In contrast to mutations in the coding sequences of a genes involved in the pathogenesis of Charcot-Marie-Tooth disease (CMT), little is known about CMT phenotypes resulting from a DNA variants located in regulatory sequences of a given " CMT gene". Charcot-Marie-Tooth type X1 disease (CMTX1) is caused by mutations in the GJB1 gene coding for an ion channel known as connexin, with a molecular mass of 32 kDa (Cx32). Only 0.01% of the GJB1 gene mutations have been reported in its 5' regulatory sequence. Pathogenic mutations occured in the internal ribosome entry site (IRES) are extremely rarely reported in human genetic disorders. To the best of our knowledge, in this study we report for the first time in an Eastern European population, two CMTX1 families in which two pathogenic mutations in the 5' regulatory sequence of the GJB1 gene (c.-529T>C and -459C>T) have been found. The two mutations identified in our study disturb the 5' UTR sequence in two different ways, by affecting the transcription factor SOX10 binding site (c.-529T>C) and by the disrupting IRES element of GJB1 gene (c.-459C>T). These regions are responsible for transcription (SOX10) and initiation of translation (IRES), respectively. On the basis of our findings that, in contrast to the most DNA sequence variants reported in untranslated regulatory regions of genes, the c.-459C>T and c.-529T>C mutations remain pathogenic in the context of different ethnic background.

A severe recessive and a mild dominant form of Charcot-Marie-Tooth disease associated with a newly identified Glu222Lys GDAP1 gene mutation

88%

Kabzińska D., Kotruchow K., Cegielska J., Hausmanowa-Petrusewicz I., Kochański A.

2014

vol. 61

issue 4

739-744

Charcot-Marie-Tooth (CMT) disease caused by mutations in the GDAP1 gene has been shown to be inherited via traits that may be either autosomal recessive (in the majority of cases) [CMT4A] or autosomal dominant [CMT2K]. CMT4A disease is characterized by an early onset, and a severe clinical course often leading to a loss of ambulation, whereas CMT2K is characterized by a mild clinical course of benign axonal neuropathy beginning even in the 6th decade of life. Clinical data from a GDAP1 mutated patient suggests that the presence of a particular mutation is associated with a certain trait of inheritance. The association of a particular GDAP1 gene mutation and a dominant or recessive trait of inheritance is of special importance for genetic counseling and the prenatal diagnostics as regards severe forms of CMT. In the present study we report on two CMT families in which a newly identified Glu222Lys mutation within the GDAP1 gene segregates both in autosomal dominant and recessive traits. Our study shows that at least some GDAP1 gene mutations may segregate with the CMT phenotype as both dominant and recessive traits. Thus, genetic counseling for CMT4A/CMT2K families requires more extensive data on GDAP1 phenotype-genotype correlations.

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2 Acta Biochimica Polonica

1 2014

1 2011

2 Kabzińska D.

2 Kochański A.

2 Kotruchow K.

1 Cegielska J.

1 Hausmanowa-Petrusewicz I.

1 Ryniewicz B.

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Two pathogenic mutations located within the 5'-regulatory sequence of the GJB1 gene affecting initiation of transcription and translation

A severe recessive and a mild dominant form of Charcot-Marie-Tooth disease associated with a newly identified Glu222Lys GDAP1 gene mutation