Family Genetic Studies Research Articles

The Presenilin-2 Loop Peptide Perturbs Intracellular Ca2+ Homeostasis and Accelerates Apoptosis

In cells undergoing apoptosis, a 22-amino-acid presenilin-2-loop peptide (PS2-LP, amino acids 308-329 in presenilin-2) is generated through cleavage of the carboxyl-terminal fragment of presenilin-2 by caspase-3. The impact of PS2-LP on the progression of apoptosis, however, is not known. Here we show that PS2-LP is a potent inducer of the mitochondrial-dependent cell death pathway when transduced as a fusion protein with HIV-TAT. Biochemical and functional studies demonstrate that TAT-PS2-LP can interact with the inositol 1,4,5-trisphosphate receptor and activate Ca(2+) release from the endoplasmic reticulum. These results indicate that PS2-LP-mediated alteration of intracellular Ca(2+) homeostasis may be linked to the acceleration of apoptosis. Therefore, targeting the function of PS2-LP could provide a useful therapeutic tool for the treatment of cancer and degenerative diseases.

Founder effect for the Ala431Glu mutation of the presenilin 1 gene causing early-onset Alzheimer’s disease in Mexican families

The etiology of Alzheimer's disease (AD) is complex. To date, molecular genetic studies in several families affected with AD have identified three genes associated with highly penetrant early-onset AD: Presenilin 1 (PSEN1), Presenilin 2 (PSEN2) and beta-amyloid precursor protein (APP); and one gene (apolipoprotein E) associated with late-onset AD. Molecular analysis of the PSEN1 gene was performed by direct sequencing of genomic DNA. The possible founder effect was investigated analyzing two highly polymorphic microsatellite markers flanking the PSEN1 gene. Twelve unrelated Mexican families with early-onset AD were analyzed. The Ala431Glu mutation in exon 12 of PSEN1 was found in nine (75%) of these families, which segregated showing autosomal dominant inheritance. Because all families bearing the mutation are from the State of Jalisco (located in Western Mexico), a founder effect was hypothesized. Microsatellite haplotype analysis suggested a common ancestor in these nine kindreds. In conclusion, the Ala431Glu mutation is a prevalent cause of early-onset familial Alzheimer's disease in families from the State of Jalisco, Mexico. Genetic evidence supports that it is a founder mutation descending from a single common ancestor. These findings have important implications for prompt diagnosis and genetic counseling for Mexican patients with familial AD from Jalisco.

An investigation of the von Willebrand factor genotype in UK patients diagnosed to have type 1 von Willebrand disease

Forty families diagnosed by UK centres to have type 1 VWD were recruited. Following review, six families were re-diagnosed to have type 2 VWD, one to have a platelet storage pool disorder, and one family was determined to be unaffected. Direct DNA sequencing of the promoter region and all exons and intronic boundaries of the VWF gene identified six mutations likely to be causative of VWD in index cases of nine of the 32 (28%) confirmed type 1 VWD families. These included R1205H (3614G > A) VWD Vicenza, P1648fsX45 (4944delT), D141G (422A > G) and three splice site mutations: 3108 + 5G > A, 7437 + 1G > A and 3379 + 1G > A. The Y1584C (4751A > G) polymorphism was present in eight additional families. No significant VWF gene mutation or polymorphism was identified in 15 of the 32 type 1VWD index cases (47%). Haplotype studies were performed using a panel of VWF polymorphisms to investigate the segregation in families of VWD phenotype with the VWF gene. In 13 of the 32 families it was likely that VWD segregated with the VWF gene. In eight families (25%) VWD clearly did not segregate with the VWF gene. We suggest that mutation screening of the VWF gene has limited general utility in genetic diagnostic and family studies in type 1 VWD. If genetic studies are performed, the incomplete penetrance and variable expressivity of type 1 VWD must be taken into account. Unless linkage of VWD phenotype with the VWF gene can be clearly demonstrated, the results of any genetic family studies should be interpreted with caution.

Family, twin, adoption, and molecular genetic studies of juvenile bipolar disorder

Juvenile bipolar disorder (JBD) has been a subject of significant research and debate. Phenotypic differences between JBD and adult-onset bipolar disorder have led researchers to question whether or not similar neuropathologic mechanisms will be found. While much is known about the genetic and environmental contributions to the adult-onset phenotype, less is known about their contributions to JBD. Here, we review family, twin, adoption, and molecular genetic studies of JBD. Behavioral genetic data suggest both genetic and environmental contributions to JBD, while molecular genetic studies find linkage to age of onset of bipolar disorder to chromosomes 12p, 14q, and 15q. Additionally, changes associated with symptom age of onset have been recently reported in the brain-derived neurotrophic factor (BDNF) and glycogen synthase kinase 3-beta (GSK3-beta) genes. We contend that further progress in discovering the precise genetic and environmental contributions to JBD may depend on advances in phenotypic refinement, an increased appreciation of comorbid conditions, and more investigation of the longitudinal course of the disorder.

Validierung eines kurzen telefonischen Tests (T3MS) für die Erkennung kognitiver Störungen

The identification of cognitive impairment in general practice requires short but accurate tests. For epidemiologic surveys and genetic family studies cognitive tests are desirable which can be administered over the telephone. We assessed the ability of a telephone version of the Modified Mini Mental State Examination (T3MS) to identify mild cognitive impairment (MCI) and mild dementia in Alzheimer's disease (AD) and compared it with the diagnostic accuracy of the conventional Mini Mental State Examination (MMSE). The study refers to 34 patients of the outpatient clinic for cognitive disorders of the technical university of Munich of whom 18 had MCI and 16 had mild dementia in AD, respectively. The study also included 14 cognitively unimpaired age-matched probands. The T3MS and MMST were validated against an expert diagnosis base on a comprehensive diagnostic workup. Statistical analysis was performed using the receiver-operator-characteristics (ROC) method. The T3MS outperformed the MMST in the distinction between MCI patients and cognitively unimpaired individuals. In the separation between cognitively unimpaired probands and patients with mild AD the T3MS achieved a sensitivity and specificity of 100 %. The T3MS is a short and practical but accurate telephone test for the identification of mild dementia in AD for use in epidemiological surveys and genetic family studies. The interview achieves higher diagnostic precision than the MMSE and contributes to a valid assessment of cognitive performance. For the identification of mild cognitive impairment, however, the T3MS was less appropriate.

Presenilin 2 regulates the systolic function of heart by modulating Ca2+signaling

Genetic studies of families with familial Alzheimer's disease have implicated presenilin 2 (PS2) in the pathogenesis of this disease. PS2 is ubiquitously expressed in various tissues including hearts. In this study, we examined cardiac phenotypes of PS2 knockout (PS2KO) mice to elucidate a role of PS2 in hearts. PS2KO mice developed normally with no evidence of cardiac hypertrophy and fibrosis. Invasive hemodynamic analysis revealed that cardiac contractility in PS2KO mice increased compared with that in their littermate controls. A study of isolated papillary muscle showed that peak amplitudes of Ca2+ transients and peak tension were significantly higher in PS2KO mice than those in their littermate controls. PS2KO mouse hearts exhibited no change in expression of calcium regulatory proteins. Since it has been demonstrated that PS2 in brain interacts with sorcin, which serves as a modulator of cardiac ryanodine receptor (RyR2), we tested whether PS2 also interacts with RyR2. Immmunoprecipitation analysis showed that PS2, sorcin, and RyR2 interact with each other in HEK-293 cells overexpressing these proteins or in mouse hearts. Immunohistochemistry of heart muscle indicated that PS2 colocalizes with RyR2 and sorcin at the Z-lines. Elevated Ca2+ attenuated the association of RyR2 with PS2, whereas the association of sorcin with PS2 was enhanced. The enhanced Ca2+ transients and contractility in PS2KO mice were observed at low extracellular [Ca2+] but not at high levels of [Ca2+]. Taken together, our results suggest that PS2 plays an important role in cardiac excitation-contraction coupling by interacting with RyR2.

Eating Disorders: From Twin Studies to Candidate Genes and Beyond

Substantial effort has been put into the exploration of the biological background of eating disorders, through family, twin and molecular genetic studies. Family studies have shown that anorexia (AN) and bulimia nervosa (BN) are strongly familial, and that familial etiologic factors appear to be shared by both disorders. Twin studies often focus on broader phenotypes or subthreshold eating disorders. These studies consistently yielded moderate to substantial heritabilities. In addition, there has been a proliferation of molecular genetic studies that focused on Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994) AN and BN. Seven linkage regions have been identified in genome-wide screens. Many genetic association studies have been performed, but no consistent association between a candidate gene and AN or BN has been reported. Larger genetic association studies and collaborations are needed to examine the involvement of several candidate genes and biological pathways in eating disorders. In addition, twin studies should be designed to assist the molecular work by further exploring genetic determinants of endophenotypes, evaluating the magnitude of contribution to liability of measured genotypes as well as environmental risk factors related to eating disorders. In this manner twin and molecular studies can move the field forward in a mutually informative way.

Eating Disorders: From Twin Studies to Candidate Genes and Beyond

AbstractSubstantial effort has been put into the exploration of the biological background of eating disorders, through family, twin and molecular genetic studies. Family studies have shown that anorexia (AN) and bulimia nervosa (BN) are strongly familial, and that familial etiologic factors appear to be shared by both disorders. Twin studies often focus on broader phenotypes or subthreshold eating disorders. These studies consistently yielded moderate to substantial heritabilities. In addition, there has been a proliferation of molecular genetic studies that focused on Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994) AN and BN. Seven linkage regions have been identified in genome-wide screens. Many genetic association studies have been performed, but no consistent association between a candidate gene and AN or BN has been reported. Larger genetic association studies and collaborations are needed to examine the involvement of several candidate genes and biological pathways in eating disorders. In addition, twin studies should be designed to assist the molecular work by further exploring genetic determinants of endophenotypes, evaluating the magnitude of contribution to liability of measured genotypes as well as environmental risk factors related to eating disorders. In this manner twin and molecular studies can move the field forward in a mutually informative way.

Ethical Issues Associated with Conducting Genetic Family Studies of Complex Disease

To examine subjects' recognition of the risks and ethical issues associated with enrollment in genetic family studies (GFS) and explore how this recognition affects their informed and voluntary participation. A cross-sectional study design including both quantitative and qualitative data was employed. Structured interviews using the Contextual Assessment Approach Questionnaire (CAA-Q) were conducted with 246 Mexican American (MA) participants. To gain in-depth understanding of questionnaire responses, semi-structured interviews with 30 participants were conducted. All participants were interviewed before their enrollment in the Family Investigation of Nephropathy and Diabetes (FIND). Subjects' average age was 56 years; 62% were females. Seventy-eight percent of participants were not formally educated beyond high school and 72% reported an annual household income of < or =20,000 dollars. Eighty-five percent agreed to provide researchers with information on relatives' ages, gender, and education. Sixty-five percent of participants were willing to provide identifiable information such as names, addresses, and phone numbers of relatives. Sixty-three percent of participants indicated that there were direct benefits (i.e., supporting research) to disclosing relatives' information. Seventy-six percent stated that there were no risks associated with participation in GFS (e.g., discrimination or confidentiality of genetic information) compared with 10% who said that there were such risks. While discussing potential risks, subjects did not consider these to influence their decision to participate. Subjects enrolled in GFS did not recognize and tended to underestimate the social and cultural risks associated with their participation in GFS. If subjects do not fully comprehend the risks, this raises questions concerning their ability to provide informed consent and to voluntarily participate. We propose a subject-centered approach that views enrollment as an active process in which subjects and recruiters give and receive information on risks and ethical issues related to participation, which enhances protection of the rights and welfare of subjects participating in GFS.

Psychiatric Comorbidity in Adult Attention Deficit Hyperactivity Disorder: Findings From Multiplex Families

Patterns of psychiatric comorbidity were assessed in adults with and without attention deficit hyperactivity disorder (ADHD) identified through a genetic study of families containing multiple children with ADHD. Lifetime ADHD and comorbid psychopathology were assessed in 435 parents of children with ADHD. Rates and mean ages at onset of comorbid psychopathology were compared in parents with lifetime ADHD, parents with persistent ADHD, and those without ADHD. Age-adjusted rates of comorbidity were compared with Kaplan-Meier survival curves. Logistic regression was used to assess additional risk factors for conditions more frequent in ADHD subjects. The parents with ADHD were significantly more likely to be unskilled workers and less likely to have a college degree. ADHD subjects had more lifetime psychopathology; 87% had at least one and 56% had at least two other psychiatric disorders, compared with 64% and 27%, respectively, in non-ADHD subjects. ADHD was associated with greater disruptive behavior, substance use, and mood and anxiety disorders and with earlier onset of major depression, dysthymia, oppositional defiant disorder, and conduct disorder. Group differences based on Kaplan-Meier age-corrected risks were consistent with those for raw frequency distributions. Male sex added risk for disruptive behavior disorders. Female sex and oppositional defiant disorder contributed to risk for depression and anxiety. ADHD was not a significant risk factor for substance use disorders when male sex, disruptive behavior disorders, and socioeconomic status were controlled. Adult ADHD is associated with significant lifetime psychiatric comorbidity that is not explained by clinical referral bias.

A family genetic study of clinical subtypes of obsessive-compulsive disorder

The results of various family studies of obsessive-compulsive disorder have varied widely, possibly because of heterogeneity in the obsessive-compulsive disorder phenotype. The current study was conducted to determine familiality of checker and washer subtypes of obsessive-compulsive disorder compared with normal controls. In this study, all available first-degree relatives of 25 checker, 34 washer and 40 psychiatrically normal control probands were interviewed directly, using structured interviews. The morbid risk of syndromal and subsyndromal obsessive-compulsive disorder was significantly greater among the relatives of checker probands (19.4%) than in the relatives of washer (8.7%) or control probands (5.4%), while the morbid risk for the relatives of washer and control probands was not significantly different. In all, 67% of the checker relatives with syndromal and subsyndromal obsessive-compulsive disorder were checkers, while 54% of the washer relatives with syndromal and subsyndromal obsessive-compulsive disorder were washers. Our study provides preliminary evidence of familiality of the checker subtype of obsessive-compulsive disorder. Future studies using patients subtyped on the basis of symptom dimensions, in larger obsessive-compulsive disorder samples, are needed, to further validate the genetic basis of obsessive-compulsive disorder.

Cone–Rod Dystrophy, Intrafamilial Variability, and Incomplete Penetrance Associated with the R172W Mutation in the Peripherin/ RDS Gene

To determine the underlying molecular genetic basis of a retinal dystrophy identified in a 5-generation family, and to examine the phenotype and degree of intrafamilial variability. Family genetic study. Nine affected individuals from a nonconsanguineous British family. Ophthalmologic examination, color vision testing, fundus photography, autofluorescence imaging, and electrophysiological assessment were performed. The clinical notes of 2 additional deceased affected family members were also reviewed. Blood samples were taken for DNA extraction, with linkage analysis being performed, and subsequent mutation screening of the peripherin/RDS gene. Linkage analysis established a disease interval on chromosome 6p, which harbored the retinal candidate gene, peripherin/RDS. The 3 coding exons of the peripherin/RDS gene were subsequently screened for mutations in affected and unaffected family members. A nonconservative missense substitution, Arg172Trp (R172W), segregated uniquely in all affected subjects. The majority of subjects carrying the R172W peripherin/RDS mutation complained of reduced central vision starting in the second or third decade, with subsequent gradual deterioration of visual acuity and color vision. Three affected individuals complained of nyctalopia. A range of macular appearances were seen, varying from a typical granular appearance to extensive macular atrophy. Autofluorescence imaging in the majority of individuals identified a highly characteristic speckled macular appearance. All affected subjects had abnormal pattern electroretinograms (ERGs) consistent with macular dysfunction and 4 subjects showed additional full-field ERG abnormalities, providing evidence of generalized retinal dysfunction. There was marked variation in the clinical phenotype in those individuals who carried the R172W peripherin/RDS mutation, ranging from severe cone-rod dystrophy to asymptomatic individuals with normal retinal function. The Arg172Trp (R172W) peripherin/RDS mutation has been previously reported to cause a fully penetrant progressive macular dystrophy with high intrafamilial and interfamilial consistency of phenotype. This is the first report describing marked intrafamilial variation associated with this mutation, including nonpenetrance. These findings are clinically important in relation to advice on prognosis and accurate genetic counseling.

Development of childhood psychiatric diseases

Most behavioural traits and child psychiatric disorders are thought to be influenced by genetic factors. The evidence for this comes from behaviour genetic family, twin and adoption studies. This contribution covers the nature of genetic and environmental influences on childhood psychiatric diseases and specifically looks at Autism and language disorders, Tourette syndrome and ADHD.

Candidate gene analysis suggests a role for fatty acid biosynthesis and regulation of the complement system in the etiology of age-related maculopathy

Age-related maculopathy (ARM) is a leading cause of visual impairment in elderly Americans and is a complex genetic disorder. Hypothesized pathways for the etiology of ARM include cholesterol and lipoprotein metabolism and transport, extracellular matrix integrity, oxidative stress and inflammatory/immunologic processes. This study investigates 21 polymorphisms within 15 candidate genes whose products function within these pathways by performing family and case-control genetic association studies using clearly affected familial cases (n=338 families, 796 individuals), clearly affected, unrelated sporadic cases (n=196) and clearly unaffected, unrelated controls (n=120). Two genes demonstrated significant association with ARM status. A Met299Val variant in the elongation of very long chain fatty acids-like 4 (ELOVL4) gene was significantly associated with ARM in the case-control allele (P=0.001), case-control genotype (P=0.001) and case-control family (P<0.0001) tests. A Tyr402His variant in exon 9 in the complement factor H (CFH) gene was also significantly associated with ARM in the case-control allele (P<0.0001), case-control genotype (P<0.0001) and case-control family (P<0.0001) tests. All of these results remain significant after adjusting for false discovery rates to control for the impact of multiple testing. In addition, the CFH variant appears to play a role in exudative and atrophic disease, whereas the ELOVL4 variant may play a greater role in exudative disease in our population. These results support a potential role for multiple pathways in the etiology of ARM, including pathways involved with fatty acid biosynthesis and the complement system.

ADAM33 Enzyme Properties and Substrate Specificity

ADAM33 is an asthma susceptibility gene recently identified through a genetic study of asthmatic families [van Eerdewegh, et al. (2002) Nature 418, 426-430]. To understand the function of the gene product, the recombinant metalloproteinase domain of human ADAM33 was purified and tested for its substrate cleavage specificity using peptides derived from beta-amyloid precursor protein (APP). A single Ala substitution at the P2 position of a 10-residue APP peptide, YEVHHQKLVF, yielded a 20-fold more efficient substrate. Terminal truncation studies identified a minimal nine-residue core (P5-P4') important for ADAM33 recognition and cleavage. Full positional scanning of the 10-mer peptide using the 19 naturally occurring l-amino acids (excluding Cys) revealed a substrate specificity profile. A strong preference for Val or Ile at P3, Ala at P2, and Gln at P1' was observed. The substrate binding model based on the X-ray structure of the ADAM33-inhibitor complex supported the observed substrate specificity profile. On the basis of this, an improved substrate was designed and a fluorescence resonance energy transfer (FRET) assay was developed using a fluorogenic derivative of this substrate. Kinetic studies confirmed that the best substrate, FRET-P2 [K(Dabcyl)YRVAFQKLAE(Edans)K], was approximately 100-fold more efficient than the wild-type APP peptide substrate, with a k(cat)/K(m) value of (3.6 +/- 0.1) x 10(4) s(-)(1) M(-)(1). Using this substrate and the FRET assay, ADAM33 enzyme activity and thermal stability were characterized. ADAM33 dependence on buffer conditions, detergents, and temperature was examined, and optimal conditions were defined. Accurate K(i) values for tissue inhibitors of metalloproteinase and small molecule compounds were obtained.

Converging evidence for attentional influences on the orthographic word form in child dyslexics

Initial confirmatory factor analyses showed that parental ratings of 209 children and youth with dyslexia in a family genetics study loaded onto factors for Inattention (Self-Regulation of Covert Attention based on two indicators—Focused and Goal-Directed Attention) and Hyperactivity (Overt Behavior based on two indicators—Motor Control and Inhibition); neither indicator is correlated with age. Structural equation modeling then evaluated a multi-level neural architecture with Covert Attention and Overt Behavior at one level, Word-Level Language Processes (Orthographic, Phonological, and Rapid Automatic Naming) at a second level, and Reading and Writing Achievement at a third level. Covert Attention, but not Overt Behavior, was significantly related to factors for orthographic coding of written words and rapid naming of orthographic stimuli, but not to the phonological coding factor for aural words. These orthographic, rapid naming, and phonological factors had significant paths to reading and writing outcomes, but the Covert Attention factor had links to reading and writing outcomes only through the mediating orthographic and rapid naming factors. Treatment and brain imaging studies provided converging evidence that attention may exert greater effects on orthographic word form than phonological word form. The neurolinguistic significance for a complex brain system, modeled at different levels of analysis, is that non-language processes such as attention may exert distal influences even though language exerts direct proximal influences on reading and writing outcomes; this claim is supported by recent physiological findings about the role of fast visual system as an attention gating mechanism in processing letter sequences. The educational significance is that instruction should direct dyslexic's attention to the orthographic units within written words to facilitate the translating of orthographic into phonological word forms.

Family genetic studies, suicide, and suicidal behavior

The extant adoption, twin, and family studies of suicide and suicidal behavior are reviewed. Suicidal behavior is highly familial, and on the basis of twin and adoption studies, heritable as well. Both completed and attempted suicide form part of the clinical phenotype that is familially transmitted, as rates of suicide attempt are elevated in the family members of suicide completers, and completion rates are elevated in the family members of attempters. A family history of suicidal behavior is associated with suicidal behavior in the proband, even after adjusting for presence of psychiatric disorders in the proband and family, indicating transmission of attempt that is distinct from family transmission of psychiatric disorder. Impulsive aggression in probands and family members is associated with family loading for suicidal behavior, and may contribute to familial transmission of suicidal behavior. Shared environment effects such as abuse, imitation, or transmission of psychopathology are other possible explanations.

Epithelial Ca2+ and Mg2+ Channels in Health and Disease

A near constancy of the extracellular Ca(2+) and Mg(2+) concentration is required for numerous physiologic functions at the organ, tissue, and cellular levels. This suggests that minor changes in the extracellular concentration of these divalents must be detected to allow the appropriate correction by the homeostatic systems. The maintenance of the Ca(2+) and Mg(2+) balance is controlled by the concerted action of intestinal absorption, renal excretion, and exchange with bone. After years of research, rapid progress was made recently in identification and characterization of the Ca(2+) and Mg(2+) transport proteins that contribute to the delicate balance of divalent cations. Expression-cloning approaches in combination with knockout mice models and genetic studies in families with a disturbed Mg(2+) balance revealed novel Ca(2+) and Mg(2+) gatekeeper proteins that belong to the super family of the transient receptor potential (TRP) channels. These epithelial Ca(2+) (TRPV5 and TRPV6) and Mg(2+) channels (TRPM6 and TRPM7) form prime targets for hormonal control of the active Ca(2+) and Mg(2+) flux from the urine space or intestinal lumen to the blood compartment. This review describes the characteristics of epithelial Ca(2+) and Mg(2+) transport in general and highlights in particular the distinctive features and the physiologic relevance of these new epithelial Ca(2+) and Mg(2+) channels in (patho)physiologic situations.

Turning on the heat

Febrile seizures (FS) occur in infancy or childhood and are associated with fever without evidence of intracranial infection or prior afebrile seizure. FS are the most common seizure disorder in children,1 affecting 2 to 5% of children by age 6 in the United States, and as many as 8.3% in Japan. After a first FS, children have a 25% to 40% recurrence risk. Genes clearly contribute to the risk of FS. FS are more common in relatives of individuals with a history of FS,2 and risks are consistently higher in monozygotic than dizygotic twins. A positive family history of FS is also a strong risk factor for FS recurrence.3 These data suggest that the predisposition to single FS and recurrence of FS are partially under genetic control. Risk for epilepsy is also increased after a first FS.4 Genetic heterogeneity is evident; recent genetic linkage studies in large pedigrees and nuclear families with FS have pointed to five chromosomal regions likely to harbor FS susceptibility genes (FEB1–FEB5; table 1).5–10⇓⇓⇓⇓⇓ Identification of the responsible genes in these regions is lacking, but has been …

Medullary cystic kidney disease type 1 in a large Native-American kindred

Background: Autosomal dominant medullary cystic kidney disease type 1 (MCKD1; Mendelian Inheritance in Man 174000) is a hereditary tubulointerstitial renal disease. For MCKD1, a locus on chromosome 1q21 is published. Although there are characteristic biopsy and imaging findings for MCKD, clinical diagnosis of this disorder is still very difficult because unique phenotypic features are not always present in individual cases. Methods: In a large Native-American kindred with apparent autosomal dominant nephropathy, clinical findings in more than 50 individuals were collected and evaluated. Haplotype analysis for 34 individuals was performed. Results: We report the difficulties establishing the diagnosis of MCKD in a large Native-American kindred solely by means of clinical criteria. This kindred shows a wider range of age of disease onset than previously reported. Gout and hypertension were common, but no patient reported symptoms of salt wasting. By means of haplotype analysis linkage was shown to the MCKD1 locus (logarithm of the odds score, 3.34). Conclusion: Establishing a diagnosis of MCKD solely on clinical findings is difficult because signs and symptoms may be subtle, renal cysts may be absent in more than 50% of affected individuals, and renal histological abnormalities are nonspecific. In patients presenting with renal insufficiency from apparent interstitial disease, a thorough family history and genetic linkage studies are required to establish a diagnosis of MCKD. We suspect MCKD is underdiagnosed and the true incidence of MCKD1 in the general population may be underestimated. No further living-related transplantation should be performed until genetic testing can exclude potentially affected donors. Background: Autosomal dominant medullary cystic kidney disease type 1 (MCKD1; Mendelian Inheritance in Man 174000) is a hereditary tubulointerstitial renal disease. For MCKD1, a locus on chromosome 1q21 is published. Although there are characteristic biopsy and imaging findings for MCKD, clinical diagnosis of this disorder is still very difficult because unique phenotypic features are not always present in individual cases. Methods: In a large Native-American kindred with apparent autosomal dominant nephropathy, clinical findings in more than 50 individuals were collected and evaluated. Haplotype analysis for 34 individuals was performed. Results: We report the difficulties establishing the diagnosis of MCKD in a large Native-American kindred solely by means of clinical criteria. This kindred shows a wider range of age of disease onset than previously reported. Gout and hypertension were common, but no patient reported symptoms of salt wasting. By means of haplotype analysis linkage was shown to the MCKD1 locus (logarithm of the odds score, 3.34). Conclusion: Establishing a diagnosis of MCKD solely on clinical findings is difficult because signs and symptoms may be subtle, renal cysts may be absent in more than 50% of affected individuals, and renal histological abnormalities are nonspecific. In patients presenting with renal insufficiency from apparent interstitial disease, a thorough family history and genetic linkage studies are required to establish a diagnosis of MCKD. We suspect MCKD is underdiagnosed and the true incidence of MCKD1 in the general population may be underestimated. No further living-related transplantation should be performed until genetic testing can exclude potentially affected donors.