Founder Effect and Estimation of the Age of the c.892C>T (p.Arg298Cys) Mutation in LMNA Associated to Charcot‐Marie‐Tooth Subtype CMT2B1 in Families from North Western Africa

CMT2B1, an axonal subtype (MIM 605588) of the Charcot‐Marie‐Tooth disease, is an autosomal recessive motor and sensory neuropathy characterized by progressive muscular and sensory loss in the distal extremities with chronic distal weakness. The genetic defect associated with the disease is, to date, a unique homozygous missense mutation, p.Arg298Cys (c.892C>T), in the LMNA gene. So far, this mutation has only been found in affected individuals originating from a restricted region of North Western Africa (northwest of Algeria and east of Morocco), strongly suggesting a founder effect. In order to address this hypothesis, genotyping of both STRs and intragenic SNPs was performed at the LMNA locus, at chromosome 1q21.2‐q21.3, in 42 individuals affected with CMT2B1 from 25 Algerian families. Our results indicate that the affected individuals share a common ancestral haplotype in a region of about 1.0 Mb (1 cM) and that the most recent common ancestor would have lived about 800–900 years ago (95% confidence interval: 550 to 1300 years).

[1]  G. Meynier.  L'Algérie des origines : de la préhistoire à l'avènement de l'islam , 2010 .

[2]  H. Worman,et al.  "Laminopathies": a wide spectrum of human diseases. , 2007, Experimental cell research.

[3]  A. Toutain,et al.  Multitissular involvement in a family with LMNA and EMD mutations , 2007, Neurology.

[4]  M. Ruberg,et al.  Autosomal recessive axonal Charcot-Marie-Tooth disease (ARCMT2): phenotype-genotype correlations in 13 Moroccan families. , 2006, Brain : a journal of neurology.

[5]  N. Lévy,et al.  Molecular genetics of autosomal-recessive axonal Charcot-Marie-Tooth neuropathies , 2007, NeuroMolecular Medicine.

[6]  M. Crawford,et al.  Genetic structure of Algerian populations , 2006, American journal of human biology : the official journal of the Human Biology Council.

[7]  C. Dodé,et al.  Prevalence and distribution of MEFV mutations among Arabs from the Maghreb patients suffering from familial Mediterranean fever. , 2006, Comptes rendus biologies.

[8]  N. Lévy,et al.  Molecular genetics of autosomal-recessive axonal Charcot-Marie-Tooth neuropathies , 2006 .

[9]  A. Dürr,et al.  LRRK2 haplotype analyses in European and North African families with Parkinson disease: a common founder for the G2019S mutation dating from the 13th century. , 2005, American journal of human genetics.

[10]  E. Bertini,et al.  Dominant LMNA mutations can cause combined muscular dystrophy and peripheral neuropathy , 2005, Journal of Neurology, Neurosurgery & Psychiatry.

[11]  M. Shy.  Charcot-Marie-Tooth disease: an update , 2004, Current opinion in neurology.

[12]  E. Génin,et al.  Estimating the age of rare disease mutations: the example of Triple-A syndrome , 2004, Journal of Medical Genetics.

[13]  G. Másson,et al.  A new mutation of the lamin A/C gene leading to autosomal dominant axonal neuropathy, muscular dystrophy, cardiac disease, and leuconychia , 2004, Journal of Medical Genetics.

[14]  P. Sindou,et al.  Phenotypic variability in autosomal recessive axonal Charcot-Marie-Tooth disease due to the R298C mutation in lamin A/C. , 2004, Brain : a journal of neurology.

[15]  K. K. Yong,et al.  Partial deficiency of the C-terminal-domain phosphatase of RNA polymerase II is associated with congenital cataracts facial dysmorphism neuropathy syndrome , 2003, Nature Genetics.

[16]  P. Sindou,et al.  The phenotypic manifestations of autosomal recessive axonalCharcot–Marie–Tooth due to a mutation in Lamin A/C gene , 2003, Neuromuscular Disorders.

[17]  C. Buresi,et al.  Haplotype study of West European and North African Unverricht-Lundborg chromosomes: evidence for a few founder mutations , 2002, Human Genetics.

[18]  M. Faerman,et al.  Genetic evidence for the expansion of Arabian tribes into the Southern Levant and North Africa. , 2002, American journal of human genetics.

[19]  C. Stewart,et al.  Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and mouse. , 2002, American journal of human genetics.

[20]  P. Underhill,et al.  High-resolution analysis of human Y-chromosome variation shows a sharp discontinuity and limited gene flow between northwestern Africa and the Iberian Peninsula. , 2001, American journal of human genetics.

[21]  A. Brice,et al.  A locus for an axonal form of autosomal recessive Charcot-Marie-Tooth disease maps to chromosome 1q21.2-q21.3. , 1999, American journal of human genetics.

[22]  C. Fizames,et al.  Genetic linkage of Meleda disease to chromosome 8qter , 1998, European Journal of Human Genetics.

[23]  L. Kunkel,et al.  Mutations in the Dystrophin-Associated Protein γ-Sarcoglycan in Chromosome 13 Muscular Dystrophy , 1995, Science.

[24]  M. Koenig,et al.  Ataxia with isolated vitamin E deficiency is caused by mutations in the α–tocopherol transfer protein , 1995, Nature Genetics.

[25]  J. Vance,et al.  Mutations in the dystrophin-associated protein gamma-sarcoglycan in chromosome 13 muscular dystrophy. , 1995, Science.

[26]  D. Labie,et al.  Anthropological approach to the heterogeneity of beta-thalassemia mutations in northern Africa. , 1994, Human biology.

[27]  J. Vance,et al.  Hereditary motor and sensory neuropathies. , 1991, Journal of medical genetics.

[28]  H. Skre,et al.  Genetic and clinical aspects of Charcot‐Marie‐Tooth's disease , 1974, Clinical genetics.