Philippe M. Frossard

Congenital Insensitivity to Pain with Anhidrosis: Novel Mutations in the TRKA (NTRK1) Gene Encoding A High-Affinity Receptor for Nerve Growth Factor

Congenital insensitivity to pain with anhidrosis (CIPA) is characterized by recurrent episodes of unexplained fever, anhidrosis (inability to sweat), absence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation. Human TRKA encodes a high-affinity tyrosine kinase receptor for nerve growth factor (NGF), a member of the neurotrophin family that induces neurite outgrowth and promotes survival of embryonic sensory and sympathetic neurons. We have recently demonstrated that TRKA is responsible for CIPA by identifying three mutations in a region encoding the intracellular tyrosine kinase domain of TRKA in one Ecuadorian and three Japanese families. We have developed a comprehensive strategy to screen for TRKA mutations, on the basis of the genes structure and organization. Here we report 11 novel mutations, in seven affected families. These are six missense mutations, two frameshift mutations, one nonsense mutation, and two splice-site mutations. Mendelian inheritance of the mutations is confirmed in six families for which parent samples are available. Two mutations are linked, on the same chromosome, to Arg85Ser and to His598Tyr;Gly607Val, hence, they probably represent double and triple mutations. The mutations are distributed in an extracellular domain, involved in NGF binding, as well as the intracellular signal-transduction domain. These data suggest that TRKA defects cause CIPA in various ethnic groups.

Mal de Meleda (MDM) caused by mutations in the gene for SLURP-1 in patients from Germany, Turkey, Palestine, and the United Arab Emirates.

Abstract. Mal de Meleda (MDM) or keratosis palmoplantaris transgrediens of Siemens is an autosomal recessive skin disorder characterized by diffuse palmoplantar keratoderma (PPK) and transgressive keratosis with an onset in early infancy. There is no associated involvement of other organs; however, a spectrum of clinical presentations with optional and variable features has been described. Mutations in the ARS (component B)-81/s gene (LY6LS) on chromosome 8q24-qter, which encodes SLURP-1, have recently been identified in patients with MDM. Here, we have analyzed four MDM families for mutations in SLURP-1. In a large Palestinian pedigree with multiple consanguinity, patients are homozygous for a new mutation that substitutes an arginine for a conserved glycine residue at positionxa086. A different mutation in Turkish patients results in the same amino acid exchange. Some remarkable similarities are seen in the clinical picture of patients from both families. Patients of an Emirati Bedouin family have a homozygous alteration of the translation initiation codon. In a German family with no known consanguinity, we have shown pseudodominant inheritance. Three affected children and their affected mother are homozygous for the missense mutation W15R. Our findings indicate that the MDM type of transgressive PPK is caused by SLURP-1 mutations in patients from various origins and demonstrate allelic heterogeneity for mutations in SLURP-1.

Human renin gene BglI dimorphism associated with hypertension in two independent populations.

The renin (REN) gene is a good candidate that could underlie an individuals genetic susceptibility to human essential hypertension (EHT). We describe here a polymerase chain reaction‐based assay for detection of a BglI dimorphic site located in the first intron of the REN gene. In this retrospective, case–control, association study, we investigated BglI allele and genotype distributions in 554 subjects (280 hypertensives and 274 normotensives) from the United Arab Emirates (UAE) – a genetically homogeneous ethnic population with no history of smoking or alcohol consumption – and in 485 hypercholesterolemic, US Caucasian subjects (250 hypertensives and 235 normotensives). A statistically significant association was found between alleles on which the BglI site is present [BglI(+)] and clinical diagnosis of EHT in the UAE sample group (odds ratio=2.69, p=0.0006), and a similar trend was observed in the US group (odds ratio=1.97, p=0.01). BglI(+) homozygous status was also investigated in the US group and found to be associated with elevated systolic and diastolic blood pressure values (respectively, 144.8±26.1 vs. 134.1±23.0 mmHg, p=0.04; and 91.0±12.5 vs. 82.2±12.7 mmHg, p=0.009).In conclusion, variations of the REN (or of a nearby) gene that may be in linkage disequilibrium with the RENBglI(+) marker could play a role in contributing to an increased individuals genetic susceptibility to EHT in the UAE population and amongst US hypercholesterolemic Caucasians. Such a genetic influence, which seems to show a recessive mode of inheritance, could also be implicated in raising both systolic and diastolic blood pressures.

Identification, by Homozygosity Mapping, of a Novel Locus for Autosomal Recessive Congenital Ichthyosis on Chromosome 17p, and Evidence for Further Genetic Heterogeneity

Autosomal recessive congenital ichthyosis (ARCI) comprises a group of severe disorders of keratinization, characterized by variable erythema and skin scaling. It is known for its high degree of genetic and clinical heterogeneity. Mutations in the gene for keratinocyte transglutaminase (TGM1) on chromosome 14q11 were shown in patients with ARCI, and a second locus was described, on chromosome 2q, in families from northern Africa. Three other loci for ARCI, on chromosomes 3p and 19p, were identified recently. We have embarked on a whole-genome scan for further loci for ARCI in four families from Germany, Turkey, and the United Arab Emirates. A novel ARCI locus was identified on chromosome 17p, between the markers at D17S938 and D17S1856, with a maximum LOD score of 3.38, at maximum recombination fraction 0.00, at D17S945, under heterogeneity. This locus is linked to the disease in the Turkish family and in the German family. Extensive genealogical studies revealed that the parents of the German patients with ARCI were eighth cousins. By homozygosity mapping, the localization of the gene could then be refined to the 8.4-cM interval between D17S938 and D17S1879. It could be shown, however, that ARCI in the two Arab families is linked neither to the new locus on chromosome 17p nor to one of the five loci known previously. Our findings give evidence of further genetic heterogeneity that is not linked to distinctive phenotypes.

Associations of angiotensinogen gene mutations with hypertension and myocardial infarction in a gulf population

To date, the human angiotensinogen (AGT) gene and some of its variants represent the best examples of genetic influences that are involved in the determination of essential hypertension (EH) and associated cardiovascular diseases (CVDs). To assess the value of genotyping AGT in a genetically homogeneous population, we carried out a retrospective, case–control study of variants M235T and T174M for putative correlations with CVDs among nationals from the United Arab Emirates (Emirati) – an ethnic group characterized by no alcohol intake and no cigarette smoking.

Congenital insensitivity to pain with anhidrosis

Congenital insensitivity to pain with anhidrosis is an autosomal-recessive disorder resulting from defective neural crest differentiation with loss of the first-order afferent system, which is responsible for pain and temperature sensation. There is also a neuronal loss in the sympathetic ganglia. Lack of sweating, hyperthermia, and infections of bones are main features of the disorder; however, contradictory results have been published regarding eccrine sweat gland innervation. A 5-year-old male patient with typical clinical manifestations of congenital insensitivity to pain with anhidrosis is presented. Immunohistochemistry with antibodies against S100 protein and neuron-specific enolase failed to reveal nerve fibers in the vicinity of the eccrine sweat glands. The roles of the nerve growth factor and tyrosine kinase receptor gene mutations in the pathogenesis of the disease are also discussed.

Deletion polymorphism in the angiotensin‐converting enzyme gene is not associated with hypertension in a Gulf Arab population

We have studied an insertion/deletion dimorphism in the human angiotensin‐converting enzyme gene amongst UAE nationals from the Abu Dhabi Emirate. Our findings show lack of association between the I/D allele marker system and clinical diagnosis of essential hypertension, suggesting that variations of the angiotensin‐converting enzyme gene do not play a major role in the determination of elevated blood pressure in this Arab population. This agrees with results reported on other ethnic groups.

Novel missense mutation in the L1 gene in a child with corpus callosum agenesis, retardation, adducted thumbs, spastic paraparesis, and hydrocephalus.

Corpus callosum agenesis, retardation, adducted thumbs, spastic paraparesis, and hydrocephalus (CRASH syndrome) is an X-linked recessive disorder caused by mutations in the neuronal cell adhesion molecule L1 (L1 CAM) gene. L1 plays a key role in axon outgrowth and pathfinding during the development of the nervous system. We describe the case of a boy from the United Arab Emirates who presented with CRASH syndrome. Scanning the L1 gene of the patient resulted in the discovery of a novel missense mutation: transition of a G (guanine) to T (thymine) at position 604 (G604→T), which results in conversion of aspartic acid to tyrosine at position 202 (D202Y) of the L1 protein. It is very likely that the cerebral dysgenesis is due to the abnormal structure and function of L1. (J Child Neurol 2000;15:239-243).

Association between a dimorphic site on chromosome 12 and clinical diagnosis of hypertension in three independent populations

With the aim of identifying putative quantitative trait loci (QTLs) involved in the regulation of blood pressure, we have carried out association studies at a candidate genetic locus ‐ a human pancreatic phospholipase A2 (PLA2) gene localized on chromosome 12. Positive associations were found between the presence of a Taq I dimorphic site localized in the first intron of this gene and hypertension in three sample populations (two from USA and one from Germany). These results indicate that a QTL implicated in determining an individuals genetic susceptibility to hypertension could be present within up to 30 cM of this human PLA2 gene.

Congenital ichthyosis, follicular atrophoderma, hypotrichosis, and hypohidrosis: A new genodermatosis?

Follicular atrophoderma is a rare anomaly observed mainly in the X-dominant form of chondrodysplasia punctata (Conradi-Hünermann-Happle syndrome) and in the X-linked dominant Bazex syndrome. We report on five Emirati sibs (three girls and two boys), 4-18 years old, with normal stature, diffuse congenital ichthyosis, patchy follicular atrophoderma, generalized and diffuse non-scarring hypotrichosis, and marked hypohidrosis. Steroid sulfatase activity, assessed in the two boys, was found to be normal. Electron microscopic studies of ichthyotic skin did not show any specific abnormality. The association of congenital diffuse ichthyosis with follicular atrophoderma and hypotrichosis has not been reported before. The patients were reminiscent of Bazex syndrome; however, ichthyosis is not a component of Bazex syndrome. We conclude that this syndrome of congenital ichthyosis with follicular atrophoderma represents a new autosomal recessive genodermatosis.