AR CMT in Ohio Old Order Amish family - GDAP1 gene mutation

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Clin Genet. 2008 May 19.

A novel mutation in the GDAP1 gene is associated with autosomal

recessive Charcot-Marie-Tooth disease in an Amish family.

Xin B, Puffenberger E, Nye L, Wiznitzer M, Wang H.

DDC Clinic for Special Needs Children, Middlefield, OH, USA.

Charcot-Marie-Tooth disease (CMT) constitutes a large group of

genetically heterogeneous disorders of the peripheral nervous system.

Autosomal recessive forms of CMT are less common in the general

population but account for the vast majority of CMT phenotypes in

communities with a high prevalence of consanguinity.

At least 10 genetic loci cause autosomal recessive forms of CMT.

Mutations in the ganglioside-induced differentiation-associated

protein 1 (GDAP1) gene are among the most frequent genetic causes of

autosomal recessive forms of CMT. To date, 28 mutations in GDAP1 gene

have been linked with the disease.

Here, we report a novel GDAP1 mutation in an Old Order Amish family

with CMT. To ascertain the Amish CMT locus, we performed a genome-

wide single nucleotide polymorphism (SNP) analysis on one of three

patients from a consanguineous pedigree. Assuming mutation

homogeneity, the analysis sought large homozygous SNP blocks that

also contained known CMT loci.

The largest homozygous SNP block in the patient was localized to

chromosome 8q13.1-21.3 and contained the GDAP1 gene. Sequence

analysis revealed a novel homozygous mutation, c.692C>T, at codon 231

(p.P231L) in exon 5 of GDAP1 in all patients.

Neither the unaffected individuals in the family nor the healthy

control samples were homozygous for this mutation. Our findings

suggested that this novel mutation in GDAP1 gene is associated with

an autosomal recessive form of CMT in Ohio Old Order Amish community.