To determine whether human X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome (IPEX; MIM 304930) is the genetic equivalent of the scurfy (sf) mouse, we sequenced the human ortholog (FOXP3) of the gene mutated in scurfy mice (Foxp3), in IPEX patients. We found four non-polymorphic mutations. Each mutation affects the forkhead/winged-helix domain of the scurfin protein, indicating that the mutations may disrupt critical DNA interactions.

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Limb-girdle muscular dystrophy (LGMD) is a clinically and genetically heterogeneous group of myopathies, including autosomal dominant and recessive forms. To date, two autosomal dominant forms have been recognized: LGMD1A, linked to chromosome 5q, and LGMD1B, associated with cardiac defects and linked to chromosome 1q11-21. Here we describe eight patients from two different families with a new form of autosomal dominant LGMD, which we propose to call LGMD1C, associated with a severe deficiency of caveolin-3 in muscle fibres. Caveolin-3 (or M-caveolin) is the muscle-specific form of the caveolin protein family, which also includes caveolin-1 and -2. Caveolins are the principal protein components of caveolae (50-100 nm invaginations found in most cell types) which represent appendages or sub-compartments of plasma membranes. We localized the human caveolin-3 gene (CAV3) to chromosome 3p25 and identified two mutations in the gene: a missense mutation in the membrane-spanning region and a micro-deletion in the scaffolding domain. These mutations may interfere with caveolin-3 oligomerization and disrupt caveolae formation at the muscle cell plasma membrane.

Idiopathic epilepsies (IEs) are a group of disorders characterized by recurrent seizures in the absence of detectable brain lesions or metabolic abnormalities. IEs include common disorders with a complex mode of inheritance and rare Mendelian traits suggesting the occurrence of several alleles with variable penetrance. We previously described a large family with a recessive form of idiopathic epilepsy, named familial infantile myoclonic epilepsy (FIME), and mapped the disease locus on chromosome 16p13.3 by linkage analysis. In the present study, we found that two compound heterozygous missense mutations (D147H and A509V) in TBC1D24, a gene of unknown function, are responsible for FIME. In situ hybridization analysis revealed that Tbc1d24 is mainly expressed at the level of the cerebral cortex and the hippocampus. By coimmunoprecipitation assay we found that TBC1D24 binds ARF6, a Ras-related family of small GTPases regulating exo-endocytosis dynamics. The main recognized function of ARF6 in the nervous system is the regulation of dendritic branching, spine formation, and axonal extension. TBC1D24 overexpression resulted in a significant increase in neurite length and arborization and the FIME mutations significantly reverted this phenotype. In this study we identified a gene mutation involved in autosomal-recessive idiopathic epilepsy, unveiled the involvement of ARF6-dependent molecular pathway in brain hyperexcitability and seizures, and confirmed the emerging role of subtle cytoarchitectural alterations in the etiology of this group of common epileptic disorders.

Unilateral motor seizures may be a specific clinical characteristic of SMEI caused by SCN1A mutations. Ten percent of SCN1A mutations are inherited from an asymptomatic or mildly affected parent, suggesting that SMEI is genetically heterogeneous. The increased frequency of familial epilepsy indicates that other genetic factors may contribute to this disorder.