Clustering and frequency of mutations in the retinal guanylate cyclase ( GUCY2D ) gene in patients with dominant cone-rod dystrophies

E —Guanylate cyclase (retGC-1) is a key enzyme in the recovery phase of phototransduc-tion in both cone and rod photoreceptor cells. 1 Upon excitation by a photon of light, an enzymatic cascade of events occurs which leads to the hydrolysis of cGMP and the closure of the cGMP gated cation channels. This results in hyperpolarisation of the plasma membrane and the generation of a signal higher up in the visual pathway. Upon closure of the ion channels, the cytosolic levels of Ca 2+ decrease because export by the Na + , K + , Ca 2+ exchanger continues. This reduced Ca 2+ concentration results in the activation of retGC by activating proteins (GCAPs) and the increased conversion of GTP to cGMP, thus restoring the level of cGMP in the photore- ceptors to their dark level. (MIM 219800) is a rare autosomal recessively inherited lysosomal storage disorder with a newborn incidence of about 1 in 100 000-200 000 in the general population (OMIM). Cystine accumu- lates in lysosomes because of dysfunctional cystinosin mediated transport of cystine out of lysosomes. The accumulation of cystine results in damage to several organs with renal damage being the most pronounced in the ﬁrst decade of life. Patients with cystinosis experience both tubular dysfunction (renal Fanconi syndrome) and glomerular deterioration. Renal Fanconi syndrome usually occurs within the ﬁrst year of life with glomerular deterioration progressing throughout the ﬁrst decade of life resulting in end stage renal failure. 1 The CTNS gene was mapped to chromosome 17p13 and subsequently isolated and characterised to have 12 exons spanning 23 kb of genomic DNA. 2 3 The most common mutation that causes cystinosis is a large deletion that encompasses exons 1-10. 4 Originally, this deletion was described as 65 kb long but the size has been recently reﬁned to 57 257 bases. 5 Forty four percent based patients homozygous this 6 E DITOR —Reports of patients with terminal de novo deletions of chromosome 15q26 are rare. Excluding cases of ring chromosome 15 formation with di V erent sized deleted chromosomal segments, only seven cases with solely distal deletions of 15q have been published. 1–7 All other cases resulted from unbalanced reciprocal translocations involving di V erent chromosomes and are therefore not compara- ble with de novo terminal deletions as described in our case. With two exceptions, all de novo cases had interstitial deletions between chromosomal bands 15q21-q25. Only the patients described by Roback et al 5 and Siebler et al 6 had terminal deletions of 15q26.1. The deletions in these patients were not investigated by FISH, but molecular genetic techniques showed the loss of one copy of the insulin-like growth factor 1 receptor gene. IGF1R is a tyrosine kinase con- taining transmembrane protein that plays an important role in cell growth control. It has been assumed that monozygosity for this gene, which maps to distal 15q26, will directly disturb this pathway and inhibit normal growth of patients. 8 including (cid:225) -galactosidase A bio-chemically 4 5 However, clinical and laboratory indicators of beneﬁt are lacking, given the slow course of the disease. for non-invasive surrogate endpoints to delineate target organ damage to monitor the e Y cacy of enzyme replacement therapies. Methods and results In the present study, we determined intima-media thickness (IMT) at the site of the radial artery, a distal, muscular, medium sized artery, in a cohort of 21 hemizygous male FD patients, with a mean age of 32 years (SD 13, range 13-56 years), compared with 21 age and sex matched normal controls. All patients were diagnosed with FD by the presence of both clinical signs and a markedly decreased (cid:225) -galactosidase A activity in leucocytes (<4 nmol/h/mg protein, normal values 25-55 nmol/ h/mg protein). No patient had end stage renal disease. Measurements of the radial artery parameters were obtained with a high precision echotracking device (NIUS 02, SMH, Bienne, Switzerland) as previously described. 6 7 Brieﬂy, the radiofrequency signal was visualised and the peaks corresponding to the blood-intima and media-adventitia interface were electroni- cally tagged and followed over several cardiac cycles. Internal diameter and wall thickness were then measured with a precision of about 10 µm. Four to six measurements were averaged. 6 7 Radial artery IMT was measured 2 cm upstream from the wrist. Compared to controls, FD patients had con-siderably higher IMT values at the site of the radial artery (ﬁg 1). IMT was twice as high in E haemochromatosis (HH), a common autosomal recessive disease of iron metabolism, is more prevalent among populations of northern Europe with an a V ected rate of 1 in 200 to 400 and a carrier frequency of around 1 in 10. 1 2 The disease is characterised by progressive iron overload, and the clinical onset usually appears after middle age. The phenotypic manifestations of HH are variable, and the severity of the disease is related to the iron loading; the most common symptoms of iron overload are fatigue, lethargy, arthropathy, and skin pigmentation, often along with more serious organ damage including cirrhosis, diabetes mellitus, myocardiopathy, and endo-crine dysfunction. The assessment of iron loading is currently based on the levels of biochemical iron markers such as transferrin saturation percentage, serum ferritin, and serum iron concentrations. However, the diagnosis of haemochromatosis can now be conﬁrmed using direct HFE mutation testing. The prognosis depends on early diagnosis and therapeutic venesections. Thus, population screening would allow early diagnosis during the asymptomatic phase and prophylactic treatment by repeated venesection to prevent the irreversible damage of iron overload, 3 but predictive diagnosis requires a well established phenotype-genotype correlation. The identiﬁcation 4 , the of direct for The the the which E DITOR —The histiocytoses represent a hetero- geneous group of disorders including both hereditary and sporadic forms. The familial form of haemophagocytic lymphohistiocytosis (HLH) was originally described by Farquhar and Claireaux 1 in 1952. The main features of this disease are fever, hepatosplenomegaly, cytopenia, hypertriglyceridaemia, hypoﬁbrino-genaemia, and central nervous system involve- ment. 2 3 Haemophagocytosis is observed at presentation or later during the course of the disease in most patients. In 1991, the Histiocyte Society deﬁned its diagnostic criteria 4 ; however, the di V erential diagnosis of HLH from other disorders may remain problemati- cal, especially in patients without familial recurrence. Linkage of the disease gene to an approximately 7.8 cM region between markers D9S1867 and D9S1790 at 9q21.3-22 was identiﬁed by homozygosity mapping in four inbred families with HLH of Pakistani de- scent. 5 Also, linkage analysis of a group of 17 families with HLH indicated mapping of a locus linked to HLH to the proximal region of the long arm of chromosome 10 in the 10q21-22 region in 10 families but not in the remaining seven, providing evidence for ge- novel in the B receptor ( EDNRB )