Respiratory syncytial virus (RSV) is the major respiratory tract pathogen in infancy. Host-related differences in susceptibility to severe RSV infection suggest that genetic factors may play a role. In this study, a candidate-gene approach was used to study whether the surfactant protein D (SP-D) gene polymorphism associates with severe RSV infection. DNA samples from 84 infants hospitalized for the treatment of RSV bronchiolitis and 93 healthy controls were analyzed. The controls were matched with the cases on the basis of sex, hospital district, date of birth (Ϯ2 wk) and gestational age at birth (Ϯ2 wk). Three biallelic SP-D gene polymorphisms were genotyped. Significant differences were observed in the SP-D allele frequencies for amino acid 11 between the RSV infants and their matched controls. The frequency of the allele coding for Met 11 (p ϭ 0.033) was increased in the severe RSV group. The frequency of the homozygous genotype Met/Met for amino acid 11 was increased in the RSV group relative to the controls, whereas the heterozygous genotype tended to be less frequent among the RSV cases than in the matched controls. Conditional logistic regression analysis was used to study whether the confounders, i.e. smoking and number of children in the family, influence the association between the homozygous SP-D genotype for methionine 11 and the risk of RSV bronchiolitis. The results further confirmed this association (p ϭ 0.028). To our knowledge, the present report provides the first evidence of a specific gene associated with susceptibility to severe RSV infection. Respiratory syncytial virus (RSV) is a major respiratory tract pathogen in early childhood. In young infants, seasonal epidemics of RSV cause 50% of the severe instances of bronchiolitis that require hospital treatment and may be fatal. Environmental factors, gender, and socioeconomic status all play a role in RSV infections, but the host-related differences in susceptibility suggest that genetic factors contribute to the risk of contracting this disease (1).Pulmonary surfactant, a complex mixture of phospholipids and surfactant proteins, lines the alveolar surface of the lung and is essential for normal respiratory function. Surfactant protein D (SP-D) was first described in association with alveolar surfactant. However, this protein does not bind to the surfactant complex and has been found elsewhere in the airways. SP-D is a collagenous C-type lectin mainly assembled as dodecamers consisting of four homotrimeric subunits. SP-D has several immunomodulatory functions, including agglutination of some viruses that cause airway disease (2).Concentrations of the surfactant components are decreased in viral bronchiolitis (3, 4). Studies with a mouse model have shown dysfunction of the surfactant complex in RSV induced pulmonary infections (5). Hickling et al. (6) showed that intranasal administration of recombinant SP-D domain to RSV-infected mice reduced the levels of lung virus by 80%, suggesting that SP-D plays a major role in clearing RSV from the lu...

The Z-line is a specialized structure connecting adjacent sarcomeres in muscle cells. ␣-Actinin cross-links actin filaments in the Z-line. Several PDZ-LIM domain proteins localize to the Z-line and interact with ␣-actinin. Actinin-associated LIM protein (ALP), C-terminal LIM domain protein (CLP36), and Z band alternatively spliced PDZ-containing protein (ZASP) have a conserved region named the ZASP-like motif (ZM) between PDZ and LIM domains. To study the interactions and function of ALP we used purified recombinant proteins in surface plasmon resonance measurements. We show that ALP and ␣-actinin 2 have two interaction sites. The ZM motif was required for the interaction of ALP internal region with the ␣-actinin rod and for targeting of ALP to the Z-line. The PDZ domain of ALP bound to the C terminus of ␣-actinin. This is the first indication that the ZM motif would have a direct role in a proteinprotein interaction. These results suggest that the two interaction sites of ALP would stabilize certain conformations of ␣-actinin 2 that would strengthen the Z-line integrity.The muscle Z-line is a highly specialized structure between adjacent sarcomeres in muscle fibers that maintain the organization of the contractile machinery (for review, see Ref. 1). ␣-Actinin is one of the major components at the Z-line. The ␣-actinin polypeptide is composed of an N-terminal actin binding domain, four spectrin repeats that form the central rod region (2, 3), and two pairs of C-terminal EF-hands (4). ␣-Actinin forms an antiparallel homodimer. ␣-Actinin cross-links actin filaments from opposite sarcomeres to the Z-line and, therefore, has a major mechanical function in keeping the sarcomeres together.Several PDZ-LIM proteins have been detected in the muscle Z-line and shown to interact with ␣-actinin (5-12). PDZ domain is a widely expressed protein-protein interaction domain (for review, see Ref. 13). PDZ-LIM proteins form one subgroup of PDZ proteins (13) and are regarded as mediators between cytoskeletal structures and signaling cascades.PDZ-LIM proteins can be divided in two subclasses; they either contain one or three LIM domains. Actinin-associated LIM protein (ALP) 1 (5, 10), C-terminal LIM domain protein (CLP36) (14) (also called hCLIM1 (15) or Elfin (16)), Reversion-induced LIM protein (RIL) (17), and Mystique (Uniprot accession number Q7Z584) belong to the first class, which has one N-terminal PDZ domain and one C-terminal LIM domain. ALP is expressed in muscle (5, 10), whereas CLP36 and RIL are mainly expressed in nonmuscle tissues (11,18,19). CLP36 shows also high expression levels in muscle (7,15,16). Enigma, Enigma homology protein, and ZASP/Cypher/Oracle form the second class, with one N-terminal PDZ domain and three C-terminal LIM domains. They all are expressed mainly in muscle (6, 9, 20 -22). An interesting feature of these seven PDZ-LIM proteins is that ALP, CLP36, and ZASP contain a conserved region, named ZASP-like motif (ZM) (SMART prediction (23) accession number SM 00735, Interpro 006643), in the internal r...

Environmental chemicals are one of the risk factors in breast cancer genesis. Cytochrome P450 (CYP) enzymes play a major role in the activation of these chemicals. Using highly specific and sensitive reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. the expression profile of all major xenobiotic metabolizing CYP forms was screened in breast tumour and surrounding tumour free (control) breast tissue in a series of 20 sample pairs obtained from females with infiltrating ductal carcinoma. The levels of CYPIAI mRNA were very low in both tumour and normal tissue. CYP1B1, CYP2B6, CYP2C, CYP2D6, CYP2E1, CYP4B1, and CYP11A1 expressions were positive in both tumours and control tissue. CYP2A6, CYP2A7, CYP2A13, CYP2F1, CYP3A4, CYP3A5. and CYP3A7 mRNAs were expressed neither in tumours nor in control tissue. These results show that several CYPs. responsible for the activation of a quite large number of procarcinogens and genotoxic estrogen metabolites. are expressed in breast tissue with a lack of qualitative differences in CYP expression at mRNA level between breast tumours and surrounding normal breast.

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The gelsolin family of proteins is a major class of actin regulatory proteins that sever, cap, and nucleate actin filaments in a calcium-dependent manner and are involved in various cellular processes. Typically, gelsolin-related proteins have three or six repeats of gelsolin-like (G) domain, and each domain plays a distinct role in severing, capping, and nucleation. The Caenorhabditis elegans gelsolin-like protein-1 (gsnl-1) gene encodes an unconventional gelsolin-related protein with four G domains. Sequence alignment suggests that GSNL-1 lacks two G domains that are equivalent to fourth and fifth G domains of gelsolin. In vitro, GSNL-1 severed actin filaments and capped the barbed end in a calcium-dependent manner. However, unlike gelsolin, GSNL-1 remained bound to the side of F-actin with a submicromolar affinity and did not nucleate actin polymerization, although it bound to G-actin with high affinity. These results indicate that GSNL-1 is a novel member of the gelsolin family of actin regulatory proteins and provide new insight into functional diversity and evolution of gelsolin-related proteins.